Compounds and compositions for inhibiting the activity of abl1, abl2 and bcr-abl1

ABSTRACT

The present invention relates to compounds of formula (I): in which Y, Y, R, R 2, R 3 and R 4 are defined in the Summary of the Invention; capable of inhibiting the activity of BCR-ABL1 and mutants thereof. The invention further provides a process for the preparation of compounds of the invention, pharmaceutical preparations comprising such compounds and methods of using such compounds in the treatment of cancers.

CROSS-REFERENCED TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.61/647,187 filed on 15 May, 2012 and U.S. Provisional Application No.61/789,145 filed on 15 Mar. 2013, each of which is hereby incorporatedby reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to compounds capable of inhibiting thetyrosine kinase enzymatic activity of the Abelson protein (ABL1), theAbelson-related protein (ABL2) and related chimeric proteins, inparticular BCR-ABL1. The invention further provides a process for thepreparation of compounds of the invention, pharmaceutical preparationscomprising such compounds and methods of using such compounds in thetreatment of cancers.

BACKGROUND OF THE INVENTION

The tyrosine kinase activity of the ABL1 protein is normally tightlyregulated, with the N-terminal cap region of the SH3 domain playing animportant role. One regulatory mechanism involves the N-terminal capglycine-2 residue being myristoylated and then interacting with amyristate binding site within the SH1 catalytic domain. A hallmark ofchronic myeloid leukemia (CML) is the Philadelphia chromosome (Ph),formed by the t(9,22) reciprocal chromosome translocation in ahaematopoietic stem cell. This chromosome carries the BCR-ABL1 oncogenewhich encodes the chimeric BCR-ABL1 protein, that lacks the N-terminalcap and has a constitutively active tyrosine kinase domain.

Although drugs that inhibit the tyrosine kinase activity of BCR-ABL1 viaan ATP-competitive mechanism, such as Gleevec®/Glivec® (imatinib),Tasigna® (nilotinib) and Sprycel® (dasatinib), are effective in thetreatment of CML, some patients relapse due to the emergence ofdrug-resistant clones, in which mutations in the SH1 domain compromiseinhibitor binding. Although Tasigna® and Sprycel® maintain efficacytowards many Gleevec-resistant mutant forms of BCR-ABL1, the mutation inwhich the threonine-315 residue is replaced by an isoleucine (T315I)remains insensitive to all three drugs and can result in CML patientsdeveloping resistance to therapy. Therefore, inhibiting BCR-ABL1mutations, such as T315I, remains an unmet medical need. In addition toCML, BCR-ABL1 fusion proteins are causative in a percentage of acutelymphocytic leukemias, and drugs targeting ABL kinase activity also haveutility in this indication.

Agents targeting the myristoyl binding site (so-called allostericinhibitors) have potential for the treatment of BCR-ABL1 disorders (J.Zhang, F. J. Adrian, W. Jahnke, S. W. Cowan-Jacob, A. G. Li, R. E.Iacob4, T. Sim, J. Powers, C. Dierks, F. Sun, G.-R. Guo, Q. Ding, B.Okram, Y. Choi, A. Wojciechowski, X. Deng, G. Liu, G. Fendrich, A.Strauss, N. Vajpai, S. Grzesiek, T. Tuntland, Y. Liu, B. Bursulaya, M.Azam, P. W. Manley, J. R. Engen, G. Q. Daley, M. Warmuth., N. S. Gray.Targeting Bcr-Abl by combining allosteric with ATP-binding-siteinhibitors. Nature 2010; 463:501-6). To prevent the emergence of drugresistance from ATP inhibitor and/or allosteric inhibitor use, acombination treatment using both types of inhibitor can be developed forthe treatment of BCR-ABL1 related disorders. In particular, the needexists for small molecules, or combinations thereof, that inhibit theactivity of BCR-ABL1 and BCR-ABL1 mutations via the ATP binding site,the myristoyl binding site or a combination of both sites.

Further, compounds of the invention as inhibitors of ABL1 kinaseactivity have the potential to be used as therapies for the treatment ofmetastatic invasive carcinomas and viral infections such as pox andEbola viruses.

The compounds from the present invention also have the potential totreat or prevent diseases or disorders associated with abnormallyactivated kinase activity of wild-type Abl, including non-malignantdiseases or disorders, such as CNS diseases in particularneurodegenerative diseases (for example Alzheimer's, Parkinson'sdiseases), motoneuroneuron diseases (amyotophic lateral sclerosis),muscular dystrophies, autoimmune and inflammatory diseases (diabetes andpulmonary fibrosis), viral infections, prion diseases.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides compounds of formula (I):

in which:

Y at each occurrence is independently selected from N and CH;

R₁ is selected from pyrimidinyl, pyridinyl, phenyl, quinoxalinyl andisoquinolinyl; wherein said pyrimidinyl, pyridinyl, phenyl, quinoxalinyland isoquinolinyl of R₁ is unsubstituted or substituted with 1 to 3 R₆groups;

R₂ is selected from pyrrolidinyl, piperidinyl, azetidinyl, morpholino,piperazinyl, 2-oxa-6-azaspiro[3.4]-octanyl,3-azabicyclo[3.1.0]hexan-3-yl,pyrrolo[3,4-c]pyrazol-5(1H,4H,6H)-yl,hexahydropyrrolo[3,4-c]pyrrolyl,6-oxo-2,7-diazaspiro[4.4]-nonanyl, 1H-pyrrolo[3,4-c]pyridinyl,1,4-oxazepan-4-yl, 2-oxooxazolidinyl, 1,4-diazepanyl,tetrahydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl,3,8-dioxa-10-azabicyclo[4.3.1]decanyl and —NR_(5a)R_(5b); wherein saidpyrrolidinyl, piperidinyl, azetidinyl, morpholino, piperazinyl,1,4-oxazepan-4-yl, pyrrolo[3,4-c]pyrazol-5(1H,4H,6H)-yl,2-oxa-6-azaspiro[3.4]-octanyl, 3-azabicyclo[3.1.0]hexan-3-yl,hexahydropyrrolo[3,4-c]pyrrolyl, 6-oxo-2,7-diazaspiro[4.4]-nonanyl,1H-pyrrolo[3,4-c]pyridinyl, 2-oxooxazolidinyl, 1,4-diazepanyl,tetrahydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl, or3,8-dioxa-10-azabicyclo[4.3.1]decanyl is unsubstituted or substitutedwith 1 to 3 R₇ groups;

R₃ is selected from hydrogen and halo;

R₄ is selected from —SF₅ and —Y₂—CF₂—Y₃;

R_(5a) is selected from hydrogen and methyl;

R_(5b) is selected from C₁₋₄alkyl and tetrahydro-2H-pyran-4-yl; whereinsaid alkyl of R_(5b) is unsubstituted or substituted with 1 to 3 groupsindependently selected from hydroxy and dimethyl-amino;

R₆ at each occurrence is independently selected from methyl, methoxy,cyano, trifluoromethyl, hydroxy-methyl, methoxy-carbonyl,2-hydroxypropan-2-yl, halo, amino, fluoro-ethyl, ethyl and cyclopropyl;

R₇ at each occurrence is independently selected from hydroxy, methyl,methoxy, hydroxy-methyl, amino, methyl-amino, amino-methyl,trifluoromethyl, 2-hydroxypropan-2-yl, methyl-carbonyl-amino,dimethyl-amino, cyano and amino-carbonyl; or two R₇ groups combine withthe atom to which they are attached to form a ring selected fromcyclopropyl, pyrrolo[3,4-c]pyrazol-5(1H,4H,6H)-yl and3-azabicyclo[3.1.0]hexan-3-yl; wherein said3-azabicyclo[3.1.0]hexan-3-yl can be optionally substituted with amino;

Y₁ is selected from N and CR₅; wherein R₅ is selected from hydrogen,methoxy and imidazolyl; wherein said imidazolyl is unsubstituted orsubstituted with methyl;

Y₂ is selected from CF₂, O and S(O)₀₋₂; and

Y₃ is selected from hydrogen, halo, methyl, difluoromethyl andtrifluoromethyl.

In a second aspect, the present invention provides a pharmaceuticalcomposition which contains a compound of formula (I) or a N-oxidederivative, individual isomers and mixture of isomers thereof; or apharmaceutically acceptable salt thereof, in admixture with one or moresuitable excipients.

In a third aspect, the present invention provides a method of treating adisease in an animal in which modulation of BCR-ABL1 activity canprevent, inhibit or ameliorate the pathology and/or symptomology of thediseases, which method comprises administering to the animal atherapeutically effective amount of a compound of formula (I) or aN-oxide derivative, individual isomers and mixture of isomers thereof,or a pharmaceutically acceptable salt thereof.

In a fourth aspect, the present invention provides the use of a compoundof formula (I) in the manufacture of a medicament for treating a diseasein an animal in which BCR-ABL1 activity contributes to the pathologyand/or symptomology of the disease.

In a fifth aspect, the present invention provides a process forpreparing compounds of formula (I) and the N-oxide derivatives, prodrugderivatives, protected derivatives, individual isomers and mixture ofisomers thereof, and the pharmaceutically acceptable salts thereof.

DEFINITIONS

The general terms used hereinbefore and hereinafter preferably havewithin the context of this disclosure the following meanings, unlessotherwise indicated, where more general terms whereever used may,independently of each other, be replaced by more specific definitions orremain, thus defining more detailed embodiments of the invention:

“Alkyl” refers to a fully saturated branched or unbranched hydrocarbonmoiety having up to 20 carbon atoms. Unless otherwise provided, alkylrefers to hydrocarbon moieties having 1 to 7 carbon atoms (C₁₋₇alkyl),or 1 to 4 carbon atoms (C₁₋₄alkyl). Representative examples of alkylinclude, but are not limited to, methyl, ethyl, n-propyl, iso-propyl,n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl,neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl,2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl and the like. Asubstituted alkyl is an alkyl group containing one or more, such as one,two or three substituents selected from halogen, hydroxy or alkoxygroups. Halo-substituted-alkyl and halo-substituted-alkoxy, can beeither straight-chained or branched and includes, methoxy, ethoxy,difluoromethyl, trifluoromethyl, pentafluoroethyl, difluoromethoxy,trifluoromethoxy, and the like.

“Aryl” means a monocyclic or fused bicyclic aromatic ring assemblycontaining six to ten ring carbon atoms. For example, aryl may be phenylor naphthyl, preferably phenyl. “Arylene” means a divalent radicalderived from an aryl group.

“BCR-ABL1” refers to a fusion protein created from the N-terminal exonsof the breakpoint cluster region (BCR) gene and the major C-terminalpart (exons 2-11) of the Abelson (ABL1) gene. The most common fusiontranscripts encode for a 210-kDa protein (p210 BCR-ABL1), although rarertranscripts encode a 190-kDa protein (p190 BCR-ABL1) and a 230-kDaprotein (p230 BCR-ABL1). The ABL1 sequences of these proteins containsan ABL1 tyrosine kinase domain which is tightly regulated in thewild-type protein, but constitutively activated in the BCR-ABL1 fusionproteins. This deregulated tyrosine kinase interacts with multiplecellular signalling pathways leading to transformation and deregulatedproliferation of the cells.

“BCR-ABL1 mutants” refers to the numerous single site mutations inBCR-ABL1 including: Glu255→Lysine, Glu255→Valine, Thr315→Isoleucine,Met244→Val, Phe317→Leu, Leu248→Val, Met343→Thr, Gly250→Ala, Met351→Thr,Gly250→Glu, Glu355→Gly, Gln252→His, Phe358→Ala, Gln252→Arg, Phe359→Val,Tyr253→His, Val379→Ile, Tyr253→Phe, Phe382→Leu, Glu255→Lys, Leu387→Met,Glu255→Val, His396→Pro, Phe311→Ile, His396→Arg, Phe311→Leu, Ser417→Tyr,Thr315→Ile, Glu459→Lys and Phe486→Ser.

Compounds of the invention are sensitive to substitution on the R₃/R₄substituted ring at the position that is ortho to the point ofattachment of the NHC(O) group. Compare, for example, the followingcompounds of formula (I). The IC₅₀ of Example 35 is <3 nM compared to achloro or dichloro substitution with an IC₅₀ of 850 nM and >10 μM,respectively:

(I) Caliper ABL1 (64-515) Compounds of formula (I) IC₅₀[μM]

0.0012 Example 35

0.85

>10

“Heteroaryl” is as defined for aryl above where one or more of the ringmembers is a heteroatom. For example C₅₋₁₀heteroaryl is a minimum of 5members as indicated by the carbon atoms but that these carbon atoms canbe replaced by a heteroatom. Consequently, C₅₋₁₀ heteroaryl includespyridyl, indolyl, indazolyl, quinoxalinyl, quinolinyl, benzofuranyl,benzopyranyl, benzothiopyranyl, benzo[1,3]dioxole, imidazolyl,benzo-imidazolyl, pyrimidinyl, furanyl, oxazolyl, isoxazolyl, triazolyl,tetrazolyl, pyrazolyl, thienyl, etc.

“Cycloalkyl” means a saturated or partially unsaturated, monocyclic,fused bicyclic or bridged polycyclic ring assembly containing the numberof ring atoms indicated. For example, C₃₋₁₀cycloalkyl includescyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

“Heterocycloalkyl” means cycloalkyl, as defined in this application,provided that one or more of the ring carbons indicated, are replaced bya moiety selected from —O—, —N═, —NR—, —C(O)—, —S—, —S(O)— or —S(O)₂—,wherein R is hydrogen, C₁₋₄alkyl or a nitrogen protecting group. Forexample, C₃₋₈heterocycloalkyl as used in this application to describecompounds of the invention includes morpholino, pyrrolidinyl,pyrrolidinyl-2-one, piperazinyl, piperidinyl, piperidinylone,1,4-dioxa-8-aza-spiro[4.5]dec-8-yl, thiomorpholino, sulfanomorpholino,sulfonomorpholino, etc.

“Halogen” (or halo) preferably represents chloro or fluoro, but may alsobe bromo or iodo.

Compounds of formula (I) may have different isomeric forms. For example,any asymmetric carbon atom may be present in the (R)-, (S)- or(R,S)-configuration, preferably in the (R)- or (S)-configuration.Substituents at a double bond or especially a ring may be present incis-(═Z—) or trans (=E—) form. The compounds may thus be present asmixtures of isomers or preferably as pure isomers, preferably as purediastereomers or pure enantiomers.

Where the plural form (e.g. compounds, salts) is used, this includes thesingular (e.g. a single compound, a single salt). “A compound” does notexclude that (e.g. in a pharmaceutical formulation) more than onecompound of the formula (I) (or a salt thereof) is present, the “a”merely representing the indefinite article. “A” can thus preferably beread as “one or more”, less preferably alternatively as “one”.

Wherever a compound or compounds of the formula (I) are mentioned, thisis further also intended to include N-oxides of such compounds and/ortautomers thereof.

The term “and/or an N-oxide thereof, a tautomer thereof and/or a(preferably pharmaceutically acceptable) salt thereof′ especially meansthat a compound of the formula (I) may be present as such or in mixturewith its N-oxide, as tautomer (e.g. due to keto-enol, lactam-lactim,amide-imidic acid or enamine-imine tautomerism) or in (e.g. equivalencyreaction caused) mixture with its tautomer, or as a salt of the compoundof the formula (I) and/or any of these forms or mixtures of two or moreof such forms.

The present invention also includes all suitable isotopic variations ofthe compounds of the invention, or pharmaceutically acceptable saltsthereof. An isotopic variation of a compound of the invention or apharmaceutically acceptable salt thereof is defined as one in which atleast one atom is replaced by an atom having the same atomic number butan atomic mass different from the atomic mass usually found in nature.Examples of isotopes that may be incorporated into the compounds of theinvention and pharmaceutically acceptable salts thereof include, but arenot limited to, isotopes of hydrogen, carbon, nitrogen and oxygen suchas ²H (D or deuterium), ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³⁵S, ¹⁸F, ³⁶Cland ¹²³I. Certain isotopic variations of the compounds of the inventionand pharmaceutically acceptable salts thereof, for example, those inwhich a radioactive isotope such as ³H or ¹⁴C is incorporated, areuseful in drug and/or substrate tissue distribution studies. Inparticular examples, ³H and ¹⁴C isotopes may be used for their ease ofpreparation and detectability. In other examples, substitution withisotopes such as ²H may afford certain therapeutic advantages resultingfrom greater metabolic stability, such as increased in vivo half-life orreduced dosage requirements. Isotopic variations of the compounds of theinvention or pharmaceutically acceptable salts thereof can generally beprepared by conventional procedures using appropriate isotopicvariations of suitable reagents.

For example, a compound of the invention can incorporate deuterium onthe pyrrolidinyl ring as shown:

This deuterated form is less prone to metabolic transformation (left,above) compared with the none deutorated form (right, above).

DESCRIPTION OF PREFERRED EMBODIMENTS

The present invention relates to compounds capable of inhibiting theactivity of BCR-ABL1 or mutants of BCR-ABL1 through the allosteric,myristoyl binding site.

In one embodiment, with respect to compounds of the invention, arecompounds of formula (Ia):

in which:

Y is selected from N and CH;

R₃ is selected from hydrogen and halo;

R₄ is selected from —SF₅ and —Y₂—CF₂—Y₃; R₆ at each occurrence isindependently selected from hydrogen, methyl, methoxy, cyano,trifluoromethyl, hydroxy-methyl, halo, amino, methoxy-carbonyl,2-hydroxypropan-2-yl, fluoro-ethyl, ethyl and cyclopropyl; R₇ at eachoccurrence is independently selected from hydroxy, methyl, methoxy,hydroxy-methyl, amino, methyl-amino, amino-methyl, trifluoromethyl,2-hydroxypropan-2-yl, methyl-carbonyl-amino, dimethyl-amino, cyano andamino-carbonyl; or two R₇ groups combine with the atom to which they areattached to form a ring selected from cyclopropyl,pyrrolo[3,4-c]pyrazol-5(1H,4H,6H)-yl and 3-azabicyclo[3.1.0]hexan-3-yl;wherein said 3-azabicyclo[3.1.0]hexan-3-yl can be optionally substitutedwith amino; Y₁ is selected from N and CR₅; wherein R₅ is selected fromhydrogen, methoxy and imidazolyl; wherein said imidazolyl isunsubstituted or substituted with methyl; Y₂ is selected from CF₂, O andS(O)₀₋₂; and Y₃ is selected from hydrogen, halo, methyl, difluoromethyland trifluoromethyl; Y₄ is selected from CR₆ and N; or thepharmaceutically acceptable salts thereof.

In another embodiment are compounds of formula (Ib):

in which: R₄ is selected from —SF₅ and —Y₂—CF₂—Y₃; R₆ at each occurrenceis independently selected from hydrogen, methyl, methoxy, cyano,trifluoromethyl, hydroxy-methyl, halo, amino, methoxy-carbonyl,2-hydroxypropan-2-yl, fluoro-ethyl, ethyl and cyclopropyl; R₇ at eachoccurrence is independently selected from hydroxy, methyl, methoxy,hydroxy-methyl, amino, methyl-amino, amino-methyl, trifluoromethyl,2-hydroxypropan-2-yl, methyl-carbonyl-amino, dimethyl-amino, cyano andamino-carbonyl; or two R₇ groups combine with the atom to which they areattached to form a ring selected from cyclopropyl,pyrrolo[3,4-c]pyrazol-5(1H,4H,6H)-yl and 3-azabicyclo[3.1.0]hexan-3-yl;wherein said 3-azabicyclo[3.1.0]hexan-3-yl can be optionally substitutedwith amino; Y₁ is selected from CH and N; Y₂ is selected from CF₂, O andS(O)₀₋₂; Y₃ is selected from hydrogen, fluoro, chloro, methyl,difluoromethyl and trifluoromethyl; or the pharmaceutically acceptablesalts thereof

In a further embodiment are compounds of formula (Ib.1):

in which: R₄ is selected from —SF₅ and —Y₂—CF₂—Y₃; R₆ at each occurrenceis independently selected from hydrogen, methyl, methoxy, cyano,trifluoromethyl, hydroxy-methyl, halo, amino, methoxy-carbonyl,2-hydroxypropan-2-yl, fluoro-ethyl, ethyl and cyclopropyl; R₇ at eachoccurrence is independently selected from hydroxy, methyl, methoxy,hydroxy-methyl, amino, methyl-amino, amino-methyl, trifluoromethyl,2-hydroxypropan-2-yl, methyl-carbonyl-amino, dimethyl-amino, cyano andamino-carbonyl; or two R₇ groups combine with the atom to which they areattached to form a ring selected from cyclopropyl,pyrrolo[3,4-c]pyrazol-5(1H,4H,6H)-yl and 3-azabicyclo[3.1.0]hexan-3-yl;wherein said 3-azabicyclo[3.1.0]hexan-3-yl can be optionally substitutedwith amino; Y₁ is selected from CH and N; Y₂ is selected from CF₂, O andS(O)₀₋₂; Y₃ is selected from hydrogen, fluoro, chloro, methyl,difluoromethyl and trifluoromethyl; or the pharmaceutically acceptablesalts thereof.

In a further embodiment are compounds selected from:

In another embodiment are compounds of formula (Ib.2):

in which: R₄ is selected from —SF₅ and —Y₂—CF₂—Y₃; R₆ at each occurrenceis independently selected from hydrogen, methyl, methoxy, cyano,trifluoromethyl, hydroxy-methyl, halo, amino, methoxy-carbonyl,2-hydroxypropan-2-yl, fluoro-ethyl, ethyl and cyclopropyl; R₇ at eachoccurrence is independently selected from hydroxy, methyl, methoxy,hydroxy-methyl, amino, methyl-amino, amino-methyl, trifluoromethyl,2-hydroxypropan-2-yl, methyl-carbonyl-amino, dimethyl-amino, cyano andamino-carbonyl; or two R₇ groups combine with the atom to which they areattached to form a ring selected from cyclopropyl and3-azabicyclo[3.1.0]hexan-3-yl; Y₁ is selected from CH and N; Y₂ isselected from CF₂, O and S(O)₀₋₂; Y₃ is selected from hydrogen, fluoro,chloro, methyl, difluoromethyl and trifluoromethyl; or thepharmaceutically acceptable salts thereof.

In a further embodiment are compounds selected from:

In another embodiment are compounds of formula (Ib.3):

in which: Y is selected from CH and N; R₃ is selected from hydrogen andhalo; R₄ is selected from —SF₅ and —Y₂—CF₂—Y₃; R₆ at each occurrence isindependently selected from hydrogen, methyl, methoxy-carbonyl,2-hydroxypropan-2-yl, methoxy, cyano, trifluoromethyl, hydroxy-methyl,halo, amino, fluoro-ethyl, ethyl and cyclopropyl; R₇ at each occurrenceis independently selected from hydroxy, methyl, methoxy, hydroxy-methyl,amino, methyl-amino, amino-methyl, trifluoromethyl,2-hydroxypropan-2-yl, methyl-carbonyl-amino, dimethyl-amino, cyano andamino-carbonyl; or two R₇ groups combine with the atom to which they areattached to form a ring selected from cyclopropyl and3-azabicyclo[3.1.0]hexan-3-yl; Y₁ is selected from CH and N; Y₂ isselected from CF₂, O and S(O)₀₋₂; Y₃ is selected from hydrogen, fluoro,chloro, methyl, difluoromethyl and trifluoromethyl; or thepharmaceutically acceptable salts thereof.

In a further embodiment are compounds selected from:

In another embodiment are compounds of formula (Ic):

in which: R₄ is selected from —SF₅ and —Y₂—CF₂—Y₃; R₆ at each occurrenceis independently selected from hydrogen, methyl, methoxy,methoxy-carbonyl, 2-hydroxypropan-2-yl, cyano, trifluoromethyl,hydroxy-methyl, halo, amino, fluoro-ethyl, ethyl and cyclopropyl; R₇ ateach occurrence is independently selected from hydroxy, methyl, methoxy,hydroxy-methyl, amino, methyl-amino, amino-methyl, trifluoromethyl,2-hydroxypropan-2-yl, methyl-carbonyl-amino, dimethyl-amino, cyano andamino-carbonyl; or two R₇ groups combine with the atom to which they areattached to form a ring selected from cyclopropyl and3-azabicyclo[3.1.0]hexan-3-yl; Y₁ is selected from CH and N; Y₂ isselected from CF₂, O and S(O)₀₋₂; Y₃ is selected from hydrogen, fluoro,chloro, methyl, difluoromethyl and trifluoromethyl; or thepharmaceutically acceptable salts thereof.

In another embodiment are compounds of formula (Ic.1):

in which: R₄ is selected from —SF₅ and —Y₂—CF₂—Y₃; R₆ at each occurrenceis independently selected from hydrogen, methyl, methoxy,methoxy-carbonyl, 2-hydroxypropan-2-yl, cyano, trifluoromethyl,hydroxy-methyl, halo, amino, fluoro-ethyl, ethyl and cyclopropyl; R₇ ateach occurrence is independently selected from hydroxy, methyl, methoxy,hydroxy-methyl, amino, methyl-amino, amino-methyl, trifluoromethyl,2-hydroxypropan-2-yl, methyl-carbonyl-amino, dimethyl-amino, cyano andamino-carbonyl; or two R₇ groups combine with the atom to which they areattached to form a ring selected from cyclopropyl and3-azabicyclo[3.1.0]hexan-3-yl; Y₁ is selected from CH and N; Y₂ isselected from CF₂, O and S(O)₀₋₂; Y₃ is selected from hydrogen, fluoro,chloro, methyl, difluoromethyl and trifluoromethyl; or thepharmaceutically acceptable salts thereof.

In a further embodiment are compounds selected from:

In another embodiment are compounds of formula (Ic.2):

in which: R₄ is selected from —SF₅ and —Y₂—CF₂—Y₃; R₆ at each occurrenceis independently selected from hydrogen, methyl, methoxy,methoxy-carbonyl, 2-hydroxypropan-2-yl, cyano, trifluoromethyl,hydroxy-methyl, halo, amino, fluoro-ethyl, ethyl and cyclopropyl; R₇ ateach occurrence is independently selected from hydroxy, methyl, methoxy,hydroxy-methyl, amino, methyl-amino, amino-methyl, trifluoromethyl,2-hydroxypropan-2-yl, methyl-carbonyl-amino, dimethyl-amino, cyano andamino-carbonyl; or two R₇ groups combine with the atom to which they areattached to form a ring selected from cyclopropyl and3-azabicyclo[3.1.0]hexan-3-yl; Y₁ is selected from CH and N; Y₂ isselected from CF₂, O and S(O)₀₋₂; Y₃ is selected from hydrogen, fluoro,chloro, methyl, difluoromethyl and trifluoromethyl; or thepharmaceutically acceptable salts thereof.

In a further embodiment are compounds selected from:

In a further embodiment are compounds of formula (Id):

in which: R₄ is selected from —SF₅ and —Y₂—CF₂—Y₃; R₆ at each occurrenceis independently selected from hydrogen, methyl, methoxy-carbonyl,2-hydroxypropan-2-yl, methoxy, cyano, trifluoromethyl, hydroxy-methyl,halo, amino, fluoro-ethyl, ethyl and cyclopropyl; R₇ at each occurrenceis independently selected from hydroxy, methyl, methoxy, hydroxy-methyl,amino, methyl-amino, amino-methyl, trifluoromethyl,2-hydroxypropan-2-yl, methyl-carbonyl-amino, dimethyl-amino, cyano andamino-carbonyl; or two R₇ groups combine with the atom to which they areattached to form a ring selected from cyclopropyl and3-azabicyclo[3.1.0]hexan-3-yl; Y₁ is selected from CH and N; Y₂ isselected from CF₂, O and S(O)₀₋₂; Y₃ is selected from hydrogen, fluoro,chloro, methyl, difluoromethyl and trifluoromethyl; or thepharmaceutically acceptable salts thereof.

In a further embodiment are compounds selected from:

In another embodiment are compounds of formula (Ie):

in which: R₄ is selected from —SF₅ and —Y₂—CF₂—Y₃; R₆ at each occurrenceis independently selected from hydrogen, methyl, methoxy,methoxy-carbonyl, 2-hydroxypropan-2-yl, cyano, trifluoromethyl,hydroxy-methyl, halo, amino, fluoro-ethyl, ethyl and cyclopropyl; R₇ ateach occurrence is independently selected from hydroxy, methyl, methoxy,hydroxy-methyl, amino, methyl-amino, amino-methyl, trifluoromethyl,2-hydroxypropan-2-yl, methyl-carbonyl-amino, dimethyl-amino, cyano andamino-carbonyl; or two R₇ groups combine with the atom to which they areattached to form a ring selected from cyclopropyl and3-azabicyclo[3.1.0]hexan-3-yl; Y₁ is selected from CH and N; Y₂ isselected from CF₂, O and S(O)₀₋₂; Y₃ is selected from hydrogen, fluoro,chloro, methyl, difluoromethyl and trifluoromethyl; or thepharmaceutically acceptable salts thereof.

In a further embodiment are compounds selected from:

In another embodiment are compounds of formula (If):

in which: R₄ is selected from —SF₅ and —Y₂—CF₂—Y₃; R₆ at each occurrenceis independently selected from hydrogen, methyl, methoxy,methoxy-carbonyl, 2-hydroxypropan-2-yl, cyano, trifluoromethyl,hydroxy-methyl, halo, amino, fluoro-ethyl, ethyl and cyclopropyl; R₇ ateach occurrence is independently selected from hydroxy, methyl, methoxy,hydroxy-methyl, amino, methyl-amino, amino-methyl, trifluoromethyl,2-hydroxypropan-2-yl, methyl-carbonyl-amino, dimethyl-amino, cyano andamino-carbonyl; or two R₇ groups combine with the atom to which they areattached to form a ring selected from cyclopropyl and3-azabicyclo[3.1.0]hexan-3-yl; Y₁ is selected from CH and N; Y₂ isselected from CF₂, O and S(O)₀₋₂; Y₃ is selected from hydrogen, fluoro,chloro, methyl, difluoromethyl and trifluoromethyl; or thepharmaceutically acceptable salts thereof.

In a further embodiment are compounds selected from:

In another embodiment are compounds of formula (Ig):

in which: R₄ is selected from —SF₅ and —Y₂—CF₂—Y₃; R₆ at each occurrenceis independently selected from hydrogen, methyl, methoxy,methoxy-carbonyl, 2-hydroxypropan-2-yl, cyano, trifluoromethyl,hydroxy-methyl, halo, amino, fluoro-ethyl, ethyl and cyclopropyl; R₇ ateach occurrence is independently selected from hydroxy, methyl, methoxy,hydroxy-methyl, amino, methyl-amino, amino-methyl, trifluoromethyl,2-hydroxypropan-2-yl, methyl-carbonyl-amino, dimethyl-amino, cyano andamino-carbonyl; or two R₇ groups combine with the atom to which they areattached to form a ring selected from cyclopropyl and3-azabicyclo[3.1.0]hexan-3-yl; Y₁ is selected from CH and N; Y₂ isselected from CF₂, O and S(O)₀₋₂; Y₃ is selected from hydrogen, fluoro,chloro, methyl, difluoromethyl and trifluoromethyl; or thepharmaceutically acceptable salts thereof.

In a further embodiment are compounds selected from:

In another embodiment are compounds of formula (Ih):

in which: R₂ is selected from morpholino, piperazinyl,2-oxa-6-azaspiro[3.4]-octanyl, hexahydropyrrolo[3,4-c]pyrrolyl,pyrrolo[3,4-c]pyrazol-5(1H,4H,6H)-yl, 6-oxo-2,7-diazaspiro[4.4]-nonanyl,1H-pyrrolo[3,4-c]pyridinyl, 2-oxooxazolidinyl, 1,4-diazepanyl,1,4-oxazepan-4-yl, tetrahydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl,3,8-dioxa-10-azabicyclo[4.3.1]decanyl, —OR_(5b) and —NR_(5a)R_(5b);wherein said morpholino, piperazinyl, 2-oxa-6-azaspiro[3.4]-octanyl,1,4-oxazepan-4-yl, pyrrolo[3,4-c]pyrazol-5(1H,4H,6H)-yl,hexahydropyrrolo[3,4-c]pyrrolyl, 6-oxo-2,7-diazaspiro[4.4]-nonanyl,1H-pyrrolo[3,4-c]pyridinyl, 2-oxooxazolidinyl, 1,4-diazepanyl,tetrahydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl, or3,8-dioxa-10-azabicyclo[4.3.1]decanyl is unsubstituted or substitutedwith 1 to 3 R₇ groups; R₄ is selected from —SF₅ and —Y₂—CF₂—Y₃; R_(5a)is selected from hydrogen and methyl; R_(5b) is selected from ethyl,hydroxy-ethyl, hydroxy-propyl, dimethyl-amino-propyl andtetrahydro-2H-pyran-4-yl; R₆ at each occurrence is independentlyselected from hydrogen, methyl, methoxy, cyano, trifluoromethyl,methoxy-carbonyl, 2-hydroxypropan-2-yl, hydroxy-methyl, halo, amino,fluoro-ethyl, ethyl and cyclopropyl; R₇ at each occurrence isindependently selected from hydroxy, methyl, methoxy, hydroxy-methyl,amino, methyl-amino, amino-methyl, trifluoromethyl,2-hydroxypropan-2-yl, methyl-carbonyl-amino, dimethyl-amino, cyano andamino-carbonyl; or two R₇ groups combine with the atom to which they areattached to form a ring selected from cyclopropyl and3-azabicyclo[3.1.0]hexan-3-yl; Y₁ is selected from CH and N; Y₂ isselected from CF₂, O and S(O)₀₋₂; Y₃ is selected from hydrogen, fluoro,chloro, methyl, difluoromethyl and trifluoromethyl; Y₄ is selected fromCR₆ and N; or the pharmaceutically acceptable salts thereof.

In a further embodiment are compounds selected from:

In another embodiment are compounds of formula (Ii):

in which: R₁ is selected from phenyl, quinoxalinyl and isoquinolinyl;wherein said phenyl, quinoxalinyl or isoquinolinyl of R₁ isunsubstituted or substituted with 1 to 3 R₆ groups; R₄ is selected from—SF₅ and —Y₂—CF₂—Y₃; R₆ at each occurrence is independently selectedfrom methyl, methoxy, cyano, trifluoromethyl, hydroxy-methyl,methoxy-carbonyl, 2-hydroxypropan-2-yl, halo, amino, fluoro-ethyl, ethyland cyclopropyl; R₇ at each occurrence is independently selected fromhydroxy, methyl, methoxy, hydroxy-methyl, amino, methyl-amino,amino-methyl, trifluoromethyl, 2-hydroxypropan-2-yl,methyl-carbonyl-amino, dimethyl-amino, cyano and amino-carbonyl; or twoR₇ groups combine with the atom to which they are attached to form aring selected from cyclopropyl and 3-azabicyclo[3.1.0]hexan-3-yl; Y₁ isselected from CH and N; Y₂ is selected from CF₂, O and S(O)₀₋₂; Y₃ isselected from hydrogen, fluoro, chloro, methyl, difluoromethyl andtrifluoromethyl; or the pharmaceutically acceptable salts thereof.

In a further embodiment are compounds selected from:

In another embodiment are compounds of formula (Ik):

in which: R₁ is selected from pyrimidinyl, pyridinyl, phenyl,quinoxalinyl and isoquinolinyl; wherein said pyrimidinyl, pyridinyl,phenyl, quinoxalinyl and isoquinolinyl of R₁ is unsubstituted orsubstituted with 1 to 3 R₆ groups; R₄ is selected from —SF₅ and—Y₂—CF₂—Y₃; R_(5a) is selected from hydrogen and methyl; R_(5b) isselected from ethyl, hydroxy-ethyl, hydroxy-propyl,dimethyl-amino-propyl and tetrahydro-2H-pyran-4-yl; R₆ at eachoccurrence is independently selected from methyl, methoxy,methoxy-carbonyl, 2-hydroxypropan-2-yl, cyano, trifluoromethyl,hydroxy-methyl, halo, amino, fluoro-ethyl, ethyl and cyclopropyl; Y₁ isselected from CH and N; Y₂ is selected from CF₂, O and S(O)₀₋₂; Y₃ isselected from hydrogen, fluoro, chloro, methyl, difluoromethyl andtrifluoromethyl; or the pharmaceutically acceptable salts thereof.

In a further embodiment are compounds selected from:

Pharmacology and Utility

On the basis of the inhibitory studies described in the “Assay” sectionbelow, a compound of formula (I) according to the invention showstherapeutic efficacy especially against disorders dependent on BCR-ABL1activity. In particular, compounds of the present invention inhibit theallosteric or myristoyl binding site of BCR-ABL1 (including wild-typeBCR-ABL1 and/or mutations thereof).

Combining an ATP-competitive inhibitor of BCR-ABL1 with an allostericinhibitor of BCR-ABL1 delays acquired resistance in BCR-ABL1+KCL-22cells, in vitro. Surprisingly, BCR-ABL1+KCL-22 cells treated every 3-4days with a compound of the invention showed an acquired resistanceafter approximately 28 days whereas these same cells treated every 3-4days with nilotinib or dasatinib showed an acquired resistance afteronly 18-21 days. Even more surprisingly, when BCR-ABL1+KCL-22 cells weretreated every 3-4 days with a combination of a compound of the inventionand either nilotinib or dasatinib, no acquired resistance was observedin at least the first 60 days. Therefore, myristoyl-binding sitecompounds of the present invention, in combination with BCR-ABL1inhibitors that bind to the ATP binding site are especially importantfor the treatment of proliferative diseases involving upregulation ofABL1 kinase activity, as in the case of BCR-ABL1 fusion proteins in CMLand subsets of other haematological malignancies such as ALL and AML.

Carcinoma cells utilize invapodia to degrade the extra cellular matrixduring tumor invasion and metastasis. ABL kinase activity is requiredfor Src-induced invapodia formation, regulating distinct stages ofinvapodia assembly and function. The compounds of the invention,therefore, as inhibitors of ABL, have the potential to be used astherapies for the treatment of metastatic invasive carcinomas.

An allosteric inhibitor of c-ABL kinase can be used to treat braincancers: including Glioblastoma which is the most common & mostaggressive malignant primary brain tumor in which the expression ofc-ABL is immunohistochemically detectable in a subset of patients(Haberler C, Gelpi E, Marosi C, Rossler K, Birner P, Budka H,Hainfellner J A Immunohistochemical analysis of platelet-derived growthfactor receptor-alpha, -beta, c-kit, c-abl, and arg proteins inglioblastoma: possible implications for patient selection for imatinibmesylate therapy. J Neurooncol. 2006 January; 76(2):105-9). However,clinical trials with Gleevec® failed in patients with glioblastoma(Reardon D A, Dresemann G, Taillibert S, Campone M, van den Bent M,Clement P, Blomquist E, Gordower L, Schultz H, Raizer J, Hau P, Easaw J,Gil M, Tonn J, Gijtenbeek A, Schlegel U, Bergstrom P, Green S, Weir A,Nikolova Z. Multicentre phase II studies evaluating imatinib plushydroxyurea in patients with progressive glioblastoma. Br J Cancer. 2009Dec. 15; 101(12):1995-2004; Razis E, Selviaridis P, Labropoulos S,Norris J L, Zhu M J, Song D D, Kalebic T, Torrens M, Kalogera-FountzilaA, Karkavelas G, Karanastasi S, Fletcher J A, Fountzilas G. Phase IIstudy of neoadjuvant imatinib in glioblastoma: evaluation of clinicaland molecular effects of the treatment. Clin Cancer Res. 2009 Oct. 1;15(19):6258-66; Dresemann G. Imatinib and hydroxyurea in pretreatedprogressive glioblastoma multiforme: a patient series. Ann Oncol. 2005October; 16(10):1702-8), possibly because of the poor brain intratumoralexposure of the drug and in the absence of disturbed blood-brain barrier(Holdhoff et al, J Neurooncol. 2010; 97(2):241-5). The transport ofGleevec® across the blood-brain barrier is in fact shown in preclinicalstudies to be limited by active efflux transporters such asP-glycoprotein. This is also the case for Dasatinib (Chen Y, Agarwal S,Shaik N M, Chen C, Yang Z, Elmquist W F. P-glycoprotein and breastcancer resistance protein influence brain distribution of dasatinib. JPharmacol Exp Ther. 2009 September; 330(3):956-63). Irradiation is knownto enhance the blood-brain barrier opening. In mouse models,glioblastoma multiforme response to Gleevec® correlated with an increasein tumor growth delay and survival when Gleevec® was administered inconjunction with daily irradiation (Geng L, Shinohara E T, Kim D, Tan J,Osusky K, Shyr Y, Hallahan D E. STI571 (Gleevec) improves tumor growthdelay and survival in irradiated mouse models of glioblastoma. Int JRadiat Oncol Biol Phys. 2006 Jan. 1; 64(1):263-71). Therefore a newc-Abl inhibitor with high brain exposure represents a solid therapeuticapproach for glioblastoma and other brain cancers.

CNS-CML: In some CML patients treated with Gleevec®, CNS Blast crisisand failure have been reported and can be explained by the poor brainexposure of Gleevec®. (Kim H J, Jung C W, Kim K, Ahn J S, Kim W S, ParkK, Ko Y H, Kang W K, Park K. Isolated blast crisis in CNS in a patientwith chronic myelogenous leukemia maintaining major cytogenetic responseafter imatinib. J Clin Oncol. 2006 Aug. 20; 24(24):4028-9; Radhika N,Minakshi M, Rajesh M, Manas B R, Deepak Kumar M. Central nervous systemblast crisis in chronic myeloid leukemia on imatinib mesylate therapy:report of two cases. Indian J Hematol Blood Transfus. 2011 March;27(1):51-4). In fact, in CML patients, Gleevec®'s concentration is infact much lower (˜100 fold) in the CNS than in plasma (Leis J F, StepanD E, Curtin P T, Ford J M, Peng B, Schubach S, Druker B J, Maziarz R T.Central nervous system failure in patients with chronic myelogenousleukemia lymphoid blast crisis and Philadelphia chromosome positiveacute lymphoblastic leukemia treated with imatinib (STI-571). LeukLymphoma. 2004 April; 45(4):695-8). Therefore, c-ABL inhibitors from thepresent invention which show a high brain exposure represent a validapproach for development of therapies against CML including CNS-CML.

Compounds of the invention can be useful in the treatment of viruses.For example, viral infections can be mediated by ABL1 kinase activity,as in the case of pox-viruses and the Ebola virus. Gleevec® and Tasigna®have been shown to stop the release of Ebola viral particles frominfected cells, in vitro (Kalman, Daniel; Bornmann, William Gerard,Methods of use of non-ATP competitive tyrosine kinase inhibitors totreat pathogenic infection, PCT Int. Appl. 2007, WO 2007002441; GarciaMayra; Cooper Arik; Shi Wei; Bornmann William; Carrion Ricardo; KalmanDaniel; Nabel Gary J. Productive Replication of Ebola Virus Is Regulatedby the c-ABL1 Tyrosine Kinase. Science translational medicine 2012;4:123ra24). Compounds of the present invention that inhibit c-ABLkinase, therefore, can be expected to reduce the pathogen's ability toreplicate.

Compounds of the invention can also be useful in the treatment of neuraldegeneration. While native c-ABL tyrosine kinase remains relativelyquiescent in healthy adult brain, it can be activated in the brain ofpatients with CNS diseases, including neurodegenerative diseases suchas, Alzheimer's disease (AD), Parkinson's disease (AD), frontotemporaldementia (FTD), Picks disease, Niemann-Pick type C disease (NPC) andother degenerative, inflammatory and autoimmune diseases and ageing.

Parkinson's disease is the second most prevalent chronicneurodegenerative disease with the most common familialautosomal-recessive form being caused by mutations in the E3 ubiquitinligase, parkin. Recent studies showed that activated c-ABL was found inthe striatum of patients with sporadic Parkinson's disease.Concomitantly, parkin was tyrosine-phosphorylated, causing loss of itsubiquitin ligase and cytoprotective activities as indicated by theaccumulation of parkin substrates (Ko H S, Lee Y, Shin J H,Karuppagounder S S, Gadad B S, Koleske A J, Pletnikova O, Troncoso J C,Dawson V L, Dawson T M. Phosphorylation by the c-Abl protein tyrosinekinase inhibits parkin's ubiquitination and protective function. ProcNatl Acad Sci USA. 2010 Sep. 21; 107(38):16691-6; Imam S Z, Zhou Q,Yamamoto A, Valente A J, Ali S F, Bains M, Roberts J L, Kahle P J, ClarkR A, Li S. Novel regulation of parkin function through c-Abl-mediatedtyrosine phosphorylation: implications for Parkinson's disease. JNeurosci. 2011 Jan. 5; 31(1):157-63). These two studies also showed thatin cell or animal models of Parkinson's disease, pharmacologicalinhibition of c-ABL kinase or genetic ABL knockdown prevented tyrosinephosphorylation of parkin and restored its E3 ligase activity andcytoprotective function both in vitro and in vivo. These resultsindicate that c-ABL-dependent tyrosine phosphorylation of parkin is amajor post-translational modification that leads to loss of parkinfunction and disease progression in sporadic PD. Therefore, the abilityof compounds of the invention to inhibit the myristate-binding site ofABL1, can be expected to offer new therapeutic opportunities forblocking the progression of Parkinson's disease.

Alzheimer's disease is characterized by two main hallmarks:extracellular deposits of the neurotoxic amyloid-β which leads toamyloid plaque development, and intracellular accumulation ofhyperphosphorylated tau which contributes to the development ofneurofibrillary tangles (NFTs).

Amyloid-β level is reduced following intrathecal treatment with Gleevec®in the brain of wild-type guinea-pigs and in cell models (Netzer W J,Dou F, Cai D, Veach D, Jean S, Li Y, Bornmann W G, Clarkson B, Xu H,Greengard P. Gleevec inhibits beta-amyloid production but not Notchcleavage. Proc Natl Acad Sci USA. 2003 Oct. 14; 100(21):12444-9). Thesame group proposed that Gleevec® achieves its amyloid-β-lowering effectvia a new mechanism preventing GSAP interaction with the gamma-secretasesubstrate, APP-CTF (He G, Luo W, Li P, Remmers C, Netzer W J, HendrickJ, Bettayeb K, Flajolet M, Gorelick F, Wennogle L P, Greengard P.Gamma-secretase activating protein is a therapeutic target forAlzheimer's disease. Nature. 2010 Sep. 2; 467(7311):95-8). In thisstudy, Gleevec®'s effect to inhibit GSAP/APP-CTF wass only seen atmicromolar concentrations. Another group showed that tyrosinephosphorylation of the intracellular domain of APP (i.e. Tyr682)regulates the amyloidogenic APP processing accelerating amyloid-βformation in vivo (Barbagallo A P, Weldon R, Tamayev R, Zhou D,Giliberto L, Foreman O, D'Adamio L. Tyr(682) in the intracellular domainof APP regulates amyloidogenic APP processing in vivo. PLoS One. 2010Nov. 16; 5(11):e15503). Other studies showed that APP istyrosine-phosphorylated in cells expressing a constitutively active formof the ABL oncogene (Zambrano N, Bruni P, Minopoli G, Mosca R, Molino D,Russo C, Schettini G, Sudol M, Russo T. The beta-amyloid precursorprotein APP is tyrosine-phosphorylated in cells expressing aconstitutively active form of the Abl protoncogene. J Biol Chem. 2001Jun. 8; 276(23):19787-92). These data together suggest a c-ABL-dependentamyloidogenic APP processing for the formation of the toxic amyloid-βpeptide and subsequent amyloid plaques. Therefore a c-ABL inhibitorwould be expected to lower amyloid plaque formation in Alzheimmer'spatients.

Tau has been shown to be phosphorylated by c-Abl kinase at tyrosines 18,197, 310, and 394 in cell models, and tau pY394 has been shown to bepresent in the lesions NFTs in the brain of AD patients.

c-ABL is activated in the brain of patients with sporadic Alzheimer'sdisease as shown by its phosphorylation either at Y412, an indicator ofactivation, which co-localizes granulovacuolar degeneration, or at T735which co-localized with the typical lesions, amyloid plaques,neurofibrillary tangles (NFTs) in addition to GVD. Amyloid-β andoxidative stress activate c. ABL kinase in neuronal cultures andintracerebral injection of fibrillar amyloid peptide leads to increasedexpression of c-ABL and a downstream effector p73. Transgenic mice(APP/Swe mouse model of AD), showed higher levels of c-ABL in theirbrain and, when these mice were treated with the c-ABL inhibitorGleevec®, tau phosphorylation was decreased in their brains. Atransgenic mouse model expressing constitutively active c-ABL inforebrain neurons exhibited neuronal loss, severe neuroinflammation, andtyrosine phosphorylation of tau in the brain (For review, seeSchlatterer S D, Acker C M, Davies P. c-Abl in neurodegenerativedisease. J Mol Neurosci. 2011 November; 45(3):445-52).

Based on all these results, evidence exists for a role for c-ABL kinasein Alzheimer's pathogenesis for development of both lesions, amyloidplaques and neurofibrillary tangles.

Further, activated c-ABL is also present in other tauopathies besidessporadic Alzheimer's including in the brain of patients withfrontotemporal dementia with N279K and P301L mutations, Pick's disease,and Guam Parkinson-dementia (Schlatterer S D, Acker C M, Davies P. c-Ablin neurodegenerative disease. J Mol Neurosci. 2011 November;45(3):445-52).

Therefore, compounds of the present invention, by inhibiting c-ABL inthe CNS, represent a valid approach for development of therapies againstAlzheimer's disease, as well as other β-amyloidoses, such as vasculardementia and other tauopathies, such as frontotemporal dementia andpicks disease.

Niemann-Pick type C (NPC) disease is a fatal autosomal recessivedisorder characterized by the accumulation of free cholesterol andglycosphingolipids in the endosomal-lysosomal system, and by aprogressive neuronal death in particular of cerebellar Purkinje neurons.In a mouse model of NPC, the proapoptotic c-ABL, the downstream targetas well as p73 target genes are expressed in the cerebellums Inhibitionof c-ABL with Gleevec® prevented from loss of Purkinje neurons, improvedneurological symptoms, and increased the survival. This prosurvivaleffect of Gleevec® correlated with reduced mRNA levels of p73proapoptotic target genes (Alvarez A R, Klein A, Castro J, Cancino G I,Amigo J, Mosqueira M, Vargas L M, Yévenes L F, Bronfman F C, Zanlungo S.Imatinib therapy blocks cerebellar apoptosis and improves neurologicalsymptoms in a mouse model of Niemann-Pick type C disease. FASEB J. 2008October; 22(10):3617-27). Therefore, compounds of the present invention,by inhibiting c-ABL kinase, represent a valid approach for thedevelopment of therapies against diseases caused by the proapoptoticc-ABL/p73 pathway, such as NPC.

In prion disease models, Gleevec® showed beneficial effects: It delayedprion neuroinvasion by inhibiting prion propagation from the peripheryto the CNS (Yun S W, Ertmer A, Flechsig E, Gilch S, Riederer P, GerlachM, Schätzl H M, Klein M A. The tyrosine kinase inhibitor imatinibmesylate delays prion neuroinvasion by inhibiting prion propagation inthe periphery. J Neurovirol. 2007 August; 13(4):328-37). Gleevec® andABL deficiency induced cellular clearance of PrPSc in prion-infectedcells (Ertmer A, Gilch S, Yun S W, Flechsig E, Klebl B, Stein-Gerlach M,Klein M A, Schätzl H M. The tyrosine kinase inhibitor STI571 inducescellular clearance of PrPSc in prion-infected cells. J Biol Chem. 2004Oct. 1; 279(40):41918-27). Therefore, novel c-Abl inhibitors from thepresent invention also represent a valid therapeutic approach for thetreatment of prion diseases such as Creutzfeldt-Jacob disease.

X-linked recessive Emery-Dreifuss muscular dystrophy is caused bymutations of emerin, a nuclear-membrane protein with roles in nucleararchitecture, gene regulation and signaling. A recent study has shownthat emerin is tyrosine-phosphorylated directly by c-ABL in cell models,and that the phosphorylation status of emerin changes emerin binding toother proteins such as BAF. This, in turn, may explain themislocalization of mutant emerin from nuclear to cytosolic compartmentsand consequently changes in downstream effector and signal integratorfor signaling pathway(s) at the nuclear envelope (Tifft K E, Bradbury KA, Wilson K L. Tyrosine phosphorylation of nuclear-membrane proteinemerin by Src, Abl and other kinases. J Cell Sci. 2009 Oct. 15; 122(Pt20):3780-90). Changes in emerin-lamin interactions during both mitosisand interphase are of relevance for the pathology of musculardystrophies. In addition, results from another study demonstrate thatGleevec® attenuates skeletal muscle dystrophy in mdx mice (Huang P, ZhaoX S, Fields M, Ransohoff R M, Zhou L. Imatinib attenuates skeletalmuscle dystrophy in mdx mice. FASEB J. 2009 August; 23(8):2539-48).

Therefore, novel c-ABL inhibitors from the present invention alsorepresent therapeutic approaches for treatment of skeletal and musculardystrophies.

Furthermore, c-ABL kinase plays a role in inflammation and oxidativestress, two mechanisms that are implicated in a variety of humandiseases ranging from acute CNS diseases, such as stroke and traumaticbrain or spinal cord injuries, chronic CNS diseases, such asAlzheimer's, Parkinson's, Huntington's and motoneuron diseases, tonon-CNS inflammatory and autoimmune diseases, such as diabetes,pulmonary fibrosis.

For example, Gleevec® prevents fibrosis in different preclinical modelsof systemic sclerosis and induces regression of established fibrosis(Akhmetshina A, Venalis P, Dees C, Busch N, Zwerina J, Schett G, DistlerO, Distler J H. Treatment with imatinib prevents fibrosis in differentpreclinical models of systemic sclerosis and induces regression ofestablished fibrosis. Arthritis Rheum. 2009 January; 60(1):219-24) andit shows antifibrotic effects in bleomycin-induced pulmonary fibrosis inmice (Aono Y, Nishioka Y, Inayama M, Ugai M, Kishi J, Uehara H, Izumi K,Sone S. Imatinib as a novel antifibrotic agent in bleomycin-inducedpulmonary fibrosis in mice. Am J Respir Crit Care Med. 2005 Jun. 1;171(11):1279-85). Another study showed that both imatinib and nilotinibattenuated bleomycin-induced acute lung injury and pulmonary fibrosis inmice (Rhee C K, Lee S H, Yoon H K, Kim S C, Lee S Y, Kwon S S, Kim Y K,Kim K H, Kim T J, Kim J W. Effect of nilotinib on bleomycin-inducedacute lung injury and pulmonary fibrosis in mice. Respiration. 2011;82(3):273-87). Although in these studies the authors were focusing onthe implication the mechanism related to PDGFRs, of interest, in thestudy by Rhee et al. (Respiration. 2011; 82(3):273-87), nilotinib whichis a more potent c-ABL inhibitor than imatinib showed superiortherapeutic antifibrotic effects, thus supporting the therapeuticapplicability of c-ABL inhibitors for treatment of human diseases withpulmonary inflammation. In another study, exposure of mice to hyperoxiaincreased c-Abl activation which is required for dynamin 2phosphorylation and reactive oxygen species production and pulmonaryleak (Singleton P A, Pendyala S, Gorshkova I A, Mambetsariev N, MoitraJ, Garcia J G, Natarajan V. Dynamin 2 and c-Abl are novel regulators ofhyperoxia-mediated NADPH oxidase activation and reactive oxygen speciesproduction in caveolin-enriched microdomains of the endothelium. J BiolChem. 2009 Dec. 11; 284(50):34964-75).

Therefore, these data indicate that new c-ABL inhibitors from thepresent invention have therapeutic applicability for treatment of humandiseases with pulmonary inflammation.

c-ABL activation by insulin, via a modification of FAK response, mayplay an important role in directing mitogenic versus metabolic insulinreceptor signaling (Genua M, Pandini G, Cassarino M F, Messina R L,Frasca F. c-Abl and insulin receptor signalling. Vitam Horm. 2009;80:77-105). c-Abl inhibitors such as Gleevec® have been shown to reversetype 1 diabetes in nonobese diabetic mice (Louvet C, Szot G L, Lang J,Lee M R, Martinier N, Bollag G, Zhu S, Weiss A, Bluestone J A. Tyrosinekinase inhibitors reverse type 1 diabetes in nonobese diabetic mice.Proc Natl Acad Sci USA. 2008 Dec. 2; 105(48):18895-900). Amelioration ofdiabetes by Gleevec® was mimicked by siRNA-mediated knockdown of c-ABLmRNA (Hägerkvist R, Sandler S, Mokhtari D, Welsh N. Amelioration ofdiabetes by imatinib mesylate (Gleevec): role of beta-cell NF-kappaBactivation and anti-apoptotic preconditioning. FASEB J. 2007 February;21(2):618-28).

Therefore, the new c-ABL inhibitors from the present invention havetherapeutic applicability for treatment of human diabetes.

A c-ABL inhibitor from the present invention can be used in combinationwith one or more of the existing treatment for the above diseases: forexample a c-ABL inhibitor from the present invention can be used incombination with Levodopa or other L-DOPA-containing medicaments or adopamine agonist for the treatment of Parkinson's disease or incombination with a cholinesterase inhibitor such as Exelon capsule ortransdermal patch for the treatment of Alzheimer's disease.

In chronic myelogeous leukemia (CML), a reciprocal balanced chromosomaltranslocation in hematopoietic stem cells (HSCs) produces the BCR-ABL1hybrid gene. The latter encodes the oncogenic BCR-ABL1 fusion protein.Whereas ABL encodes a tightly regulated protein tyrosine kinase, whichplays a fundamental role in regulating cell proliferation, adherence andapoptosis, the BCR-ABL1 fusion gene encodes as constitutively activatedkinase. This activated kinase transforms HSCs to produce a phenotypeexhibiting deregulated clonal proliferation, reduced capacity to adhereto the bone marrow stroma and a reduced apoptotic response to mutagenicstimuli, resulting in progressively more malignant transformations. There-suiting granulocytes fail to develop into mature lymphocytes and arereleased into the circulation, leading to a deficiency in the maturecells and increased susceptibility to infection. ATP-competitiveinhibitors of BCR-ABL1 have been demonstrated to prevent the kinase fromactivating mitogenic and anti-apoptotic pathways (for example, P-3kinase and STATS), leading to the death of the BCR-ABL1 phenotype cellsand thereby providing an effective therapy against CML. The compounds ofthe invention, as BCR-ABL1 inhibitors, including mutants thereof, arethus especially appropriate for the therapy of diseases related to itsover-expression, such as ALL or CML leukemias.

Compounds of the invention have also been demonstrated to haveanti-tumor activity, in vivo: The in vivo antitumor activity is tested,for example using leukemic cell lines such as Ba/F3-BCR-ABL1, KC-22,K-562, MEG-01, KYO-1, LAMA-84, KU812, EM-2, CML-T1, BV-173, or ALL-SIL.

The present invention includes a method to treat cancer, comprisingadministering to a subject in need of such treatment an effective amountof a compound of the invention or a pharmaceutical composition.

A further embodiment comprises administering to the subject anadditional therapeutic agent.

In a further embodiment, the additional therapeutic agent is a differentBCR-ABL1 inhibitor selected from imatinib, nilotinib, dasatinib,dosutinib, ponatinib and bafetinib.

In another embodiment is a method to treat a condition mediated byBCR-ABL1, comprising administering to a subject in need thereof aneffective amount of a compound of the invention or a pharmaceuticalcomposition.

In a further embodiment, the BCR-ABL1 contains one or more mutations(UJane F. Apperley. Part 1: Mechanism of resistance to imatinib inchronic myeloid leukaemia. Lancet Oncology 2007; 8:1018). Examples ofsuch mutations include V299L, T315I, F317I, F317L, Y253F, Y253H, E255K,E255V, F359C and F359V.

In certain embodiments, the present invention relates to theaforementioned method, wherein said compound is administeredparenterally.

In certain embodiments, the present invention relates to theaforementioned method, wherein said compound is administeredintramuscularly, intravenously, subcutaneously, orally, pulmonary,intrathecally, topically or intranasally.

In certain embodiments, the present invention relates to theaforementioned method, wherein said compound is administeredsystemically.

In certain embodiments, the present invention relates to theaforementioned method, wherein said patient is a mammal.

In certain embodiments, the present invention relates to theaforementioned method, wherein said patient is a primate.

In certain embodiments, the present invention relates to theaforementioned method, wherein said patient is a human.

In another aspect, the present invention relates to a method of treatingan ABL1/BCR-ABL1-mediated disorder, comprising the step of:administering to a patient in need thereof a therapeutically effectiveamount of a chemothereutic agent in combination with a therapeuticallyeffective amount of a compound of compound of formula (I) as defined inthe Summary of the Invention.

In another aspect, the present invention relates to a method of treatinga ABL1/BCR-ABL1-mediated disorder, comprising the step of: administeringto a patient in need thereof a therapeutically effective amount of achemothereutic agent in combination with a therapeutically effectiveamount of a compound of compound of formula (I).

Pharmaceutical Compositions

In another aspect, the present invention provides pharmaceuticallyacceptable compositions which comprise a therapeutically-effectiveamount of one or more of the compounds described above, formulatedtogether with one or more pharmaceutically acceptable carriers(additives) and/or diluents. As described in detail below, thepharmaceutical compositions of the present invention may be speciallyformulated for administration in solid or liquid form, including thoseadapted for the following: (1) oral administration, for example,drenches (aqueous or non-aqueous solutions or suspensions), tablets,e.g., those targeted for buccal, sublingual, and systemic absorption,boluses, powders, granules, pastes for application to the tongue; (2)parenteral administration, for example, by subcutaneous, intramuscular,intravenous or epidural injection as, for example, a sterile solution orsuspension, or sustained-release formulation; (3) topical application,for example, as a cream, ointment, or a controlled-release patch orspray applied to the skin; (4) intravaginally or intrarectally, forexample, as a pessary, cream or foam; (5) sublingually; (6) ocularly;(7) transdermally; (8) nasally; (9) pulmonary; or (10) intrathecally.

The phrase “therapeutically-effective amount” as used herein means thatamount of a compound, material, or composition comprising a compound ofthe present invention which is effective for producing some desiredtherapeutic effect in at least a sub-population of cells in an animal ata reasonable benefit/risk ratio applicable to any medical treatment.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The phrase “pharmaceutically-acceptable carrier” as used herein means apharmaceutically-acceptable material, composition or vehicle, such as aliquid or solid filler, diluent, excipient, manufacturing aid (e.g.,lubricant, talc magnesium, calcium or zinc stearate, or steric acid), orsolvent encapsulating material, involved in carrying or transporting thesubject compound from one organ, or portion of the body, to anotherorgan, or portion of the body. Each carrier must be “acceptable” in thesense of being compatible with the other ingredients of the formulationand not injurious to the patient. Some examples of materials which canserve as pharmaceutically-acceptable carriers include: (1) sugars, suchas lactose, glucose and sucrose; (2) starches, such as corn starch andpotato starch; (3) cellulose, and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4)powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients,such as cocoa butter and suppository waxes; (9) oils, such as peanutoil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil andsoybean oil; (10) glycols, such as propylene glycol; (11) polyols, suchas glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters,such as ethyl oleate and ethyl laurate; (13) agar; (14) bufferingagents, such as magnesium hydroxide and aluminum hydroxide; (15) alginicacid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer'ssolution; (19) ethyl alcohol; (20) pH buffered solutions; (21)polyesters, polycarbonates and/or polyanhydrides; and (22) othernon-toxic compatible substances employed in pharmaceutical formulations.

As set out above, certain embodiments of the present compounds maycontain a basic functional group, such as amino or alkylamino, and are,thus, capable of forming pharmaceutically-acceptable salts withpharmaceutically-acceptable acids. The term “pharmaceutically-acceptablesalts” in this respect, refers to the relatively non-toxic, inorganicand organic acid addition salts of compounds of the present invention.These salts can be prepared in situ in the administration vehicle or thedosage form manufacturing process, or by separately reacting a purifiedcompound of the invention in its free base form with a suitable organicor inorganic acid, and isolating the salt thus formed during subsequentpurification. Representative salts include the hydrobromide,hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate,valerate, oleate, palmitate, stearate, laurate, benzoate, lactate,phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate,napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonatesalts and the like. (See, for example, Berge et al. (1977)“Pharmaceutical Salts”, J. Pharm. Sci. 66:1-19).

The pharmaceutically acceptable salts of the subject compounds includethe conventional nontoxic salts or quaternary ammonium salts of thecompounds, e.g., from non-toxic organic or inorganic acids. For example,such conventional nontoxic salts include those derived from inorganicacids such as hydrochloride, hydrobromic, sulfuric, sulfamic,phosphoric, nitric, and the like; and the salts prepared from organicacids such as acetic, propionic, succinic, glycolic, stearic, lactic,malic, tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic,phenylacetic, glutamic, benzoic, salicyclic, sulfanilic,2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isothionic, and the like.

In other cases, the compounds of the present invention may contain oneor more acidic functional groups and, thus, are capable of formingpharmaceutically-acceptable salts with pharmaceutically-acceptablebases. The term “pharmaceutically-acceptable salts” in these instancesrefers to the relatively non-toxic, inorganic and organic base additionsalts of compounds of the present invention. These salts can likewise beprepared in situ in the administration vehicle or the dosage formmanufacturing process, or by separately reacting the purified compoundin its free acid form with a suitable base, such as the hydroxide,carbonate or bicarbonate of a pharmaceutically-acceptable metal cation,with ammonia, or with a pharmaceutically-acceptable organic primary,secondary or tertiary amine. Representative alkali or alkaline earthsalts include the lithium, sodium, potassium, calcium, magnesium, andaluminum salts and the like. Representative organic amines useful forthe formation of base addition salts include ethylamine, diethylamine,ethylenediamine, ethanolamine, diethanolamine, piperazine and the like.(See, for example, Berge et al., supra)

Wetting agents, emulsifiers and lubricants, such as sodium laurylsulfate and magnesium stearate, as well as coloring agents, releaseagents, coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the compositions.

Examples of pharmaceutically-acceptable antioxidants include: (1) watersoluble antioxidants, such as ascorbic acid, cysteine hydrochloride,sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2)oil-soluble antioxidants, such as ascorbyl palmitate, butylatedhydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propylgallate, alpha-tocopherol, and the like; and (3) metal chelating agents,such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol,tartaric acid, phosphoric acid, and the like.

Formulations of the present invention include those suitable for oral,nasal, topical (including buccal and sublingual), rectal, vaginal and/orparenteral administration. The formulations may conveniently bepresented in unit dosage form and may be prepared by any methods wellknown in the art of pharmacy. The amount of active ingredient which canbe combined with a carrier material to produce a single dosage form willvary depending upon the host being treated, the particular mode ofadministration. The amount of active ingredient which can be combinedwith a carrier material to produce a single dosage form will generallybe that amount of the compound which produces a therapeutic effect.Generally, out of one hundred percent, this amount will range from about0.1 percent to about ninety-nine percent of active ingredient,preferably from about 5 percent to about 70 percent, most preferablyfrom about 10 percent to about 30 percent.

In certain embodiments, a formulation of the present invention comprisesan excipient selected from the group consisting of cyclodextrins,celluloses, liposomes, micelle forming agents, e.g., bile acids, andpolymeric carriers, e.g., polyesters and polyanhydrides; and a compoundof the present invention. In certain embodiments, an aforementionedformulation renders orally bioavailable a compound of the presentinvention.

Methods of preparing these formulations or compositions include the stepof bringing into association a compound of the present invention withthe carrier and, optionally, one or more accessory ingredients. Ingeneral, the formulations are prepared by uniformly and intimatelybringing into association a compound of the present invention withliquid carriers, or finely divided solid carriers, or both, and then, ifnecessary, shaping the product.

Formulations of the invention suitable for oral administration may be inthe form of capsules, cachets, pills, tablets, lozenges (using aflavored basis, usually sucrose and acacia or tragacanth), powders,granules, or as a solution, suspension or solid dispersion in an aqueousor non-aqueous liquid, or as an oil-in-water or water-in-oil liquidemulsion, or as an elixir or syrup, or as pastilles (using an inertbase, such as gelatin and glycerin, or sucrose and acacia) and/or asmouth washes and the like, each containing a predetermined amount of acompound of the present invention as an active ingredient. A compound ofthe present invention may also be administered as a bolus, electuary orpaste.

In solid dosage forms of the invention for oral administration(capsules, tablets, pills, dragees, powders, granules, trouches and thelike), the active ingredient is mixed with one or morepharmaceutically-acceptable carriers, such as sodium citrate ordicalcium phosphate, and/or any of the following: (1) fillers orextenders, such as starches, lactose, sucrose, glucose, mannitol, and/orsilicic acid; (2) binders, such as, for example, carboxymethylcellulose,alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3)humectants, such as glycerol; (4) disintegrating agents, such asagar-agar, calcium carbonate, potato or tapioca starch, alginic acid,certain silicates, and sodium carbonate; (5) solution retarding agents,such as paraffin; (6) absorption accelerators, such as quaternaryammonium compounds and surfactants, such as poloxamer and sodium laurylsulfate; (7) wetting agents, such as, for example, cetyl alcohol,glycerol monostearate, and non-ionic surfactants; (8) absorbents, suchas kaolin and bentonite clay; (9) lubricants, such as talc, calciumstearate, magnesium stearate, solid polyethylene glycols, sodium laurylsulfate, zinc stearate, sodium stearate, stearic acid, and mixturesthereof; (10) coloring agents; and (11) controlled release agents suchas crospovidone or ethyl cellulose. In the case of capsules, tablets andpills, the pharmaceutical compositions may also comprise bufferingagents. Solid compositions of a similar type may also be employed asfillers in soft and hard-shelled gelatin capsules using such excipientsas lactose or milk sugars, as well as high molecular weight polyethyleneglycols and the like.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared usingbinder (for example, gelatin or hydroxypropylmethyl cellulose),lubricant, inert diluent, preservative, disintegrant (for example,sodium starch glycolate or cross-linked sodium carboxymethyl cellulose),surface-active or dispersing agent. Molded tablets may be made bymolding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

The tablets, and other solid dosage forms of the pharmaceuticalcompositions of the present invention, such as dragees, capsules, pillsand granules, may optionally be scored or prepared with coatings andshells, such as enteric coatings and other coatings well known in thepharmaceutical-formulating art. They may also be formulated so as toprovide slow or controlled release of the active ingredient thereinusing, for example, hydroxypropylmethyl cellulose in varying proportionsto provide the desired release profile, other polymer matrices,liposomes and/or microspheres. They may be formulated for rapid release,e.g., freeze-dried. They may be sterilized by, for example, filtrationthrough a bacteria-retaining filter, or by incorporating sterilizingagents in the form of sterile solid compositions which can be dissolvedin sterile water, or some other sterile injectable medium immediatelybefore use. These compositions may also optionally contain opacifyingagents and may be of a composition that they release the activeingredient(s) only, or preferentially, in a certain portion of thegastrointestinal tract, optionally, in a delayed manner. Examples ofembedding compositions which can be used include polymeric substancesand waxes. The active ingredient can also be in micro-encapsulated form,if appropriate, with one or more of the above-described excipients.

Liquid dosage forms for oral administration of the compounds of theinvention include pharmaceutically acceptable emulsions, microemulsions,solutions, suspensions, syrups and elixirs. In addition to the activeingredient, the liquid dosage forms may contain inert diluents commonlyused in the art, such as, for example, water or other solvents,solubilizing agents and emulsifiers, such as ethyl alcohol, isopropylalcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzylbenzoate, propylene glycol, 1,3-butylene glycol, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor and sesame oils),glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acidesters of sorbitan, and mixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring, coloring, perfuming and preservative agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, and mixturesthereof.

Formulations of the pharmaceutical compositions of the invention forrectal or vaginal administration may be presented as a suppository,which may be prepared by mixing one or more compounds of the inventionwith one or more suitable nonirritating excipients or carrierscomprising, for example, cocoa butter, polyethylene glycol, asuppository wax or a salicylate, and which is solid at room temperature,but liquid at body temperature and, therefore, will melt in the rectumor vaginal cavity and release the active compound.

Formulations of the present invention which are suitable for vaginaladministration also include pessaries, tampons, creams, gels, pastes,foams or spray formulations containing such carriers as are known in theart to be appropriate.

Dosage forms for the topical or transdermal administration of a compoundof this invention include powders, sprays, ointments, pastes, creams,lotions, gels, solutions, patches and inhalants. The active compound maybe mixed under sterile conditions with a pharmaceutically-acceptablecarrier, and with any preservatives, buffers, or propellants which maybe required.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, excipients, such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to a compound of thisinvention, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants, suchas chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons,such as butane and propane.

Transdermal patches have the added advantage of providing controlleddelivery of a compound of the present invention to the body. Such dosageforms can be made by dissolving or dispersing the compound in the propermedium. Absorption enhancers can also be used to increase the flux ofthe compound across the skin. The rate of such flux can be controlled byeither providing a rate controlling membrane or dispersing the compoundin a polymer matrix or gel.

Ophthalmic formulations, eye ointments, powders, solutions and the like,are also contemplated as being within the scope of this invention.

Pharmaceutical compositions of this invention suitable for parenteraladministration comprise one or more compounds of the invention incombination with one or more pharmaceutically-acceptable sterileisotonic aqueous or nonaqueous solutions, dispersions, suspensions oremulsions, or sterile powders which may be reconstituted into sterileinjectable solutions or dispersions just prior to use, which may containsugars, alcohols, antioxidants, buffers, bacteriostats, solutes whichrender the formulation isotonic with the blood of the intended recipientor suspending or thickening agents.

Examples of suitable aqueous and nonaqueous carriers which may beemployed in the pharmaceutical compositions of the invention includewater, ethanol, polyols (such as glycerol, propylene glycol,polyethylene glycol, and the like), and suitable mixtures thereof,vegetable oils, such as olive oil, and injectable organic esters, suchas ethyl oleate. Proper fluidity can be maintained, for example, by theuse of coating materials, such as lecithin, by the maintenance of therequired particle size in the case of dispersions, and by the use ofsurfactants.

These compositions may also contain adjuvants such as preservatives,wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms upon the subject compounds may be ensuredby the inclusion of various antibacterial and antifungal agents, forexample, paraben, chlorobutanol, phenol sorbic acid, and the like. Itmay also be desirable to include isotonic agents, such as sugars, sodiumchloride, and the like into the compositions. In addition, prolongedabsorption of the injectable pharmaceutical form may be brought about bythe inclusion of agents which delay absorption such as aluminummonostearate and gelatin.

In some cases, in order to prolong the effect of a drug, it is desirableto slow the absorption of the drug from subcutaneous or intramuscularinjection. This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material having poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolutionwhich, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally-administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle.

Injectable depot forms are made by forming microencapsule matrices ofthe subject compounds in biodegradable polymers such aspolylactide-polyglycolide. Depending on the ratio of drug to polymer,and the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides). Depot injectableformulations are also prepared by entrapping the drug in liposomes ormicroemulsions which are compatible with body tissue.

When the compounds of the present invention are administered aspharmaceuticals, to humans and animals, they can be given per se or as apharmaceutical composition containing, for example, 0.1 to 99% (morepreferably, 10 to 30%) of active ingredient in combination with apharmaceutically acceptable carrier.

The preparations of the present invention may be given orally,parenterally, topically, or rectally. They are of course given in formssuitable for each administration route. For example, they areadministered in tablets or capsule form, by injection, inhalation, eyelotion, ointment, suppository, etc. administration by injection,infusion or inhalation; topical by lotion or ointment; and rectal bysuppositories. Oral administrations are preferred.

The phrases “parenteral administration” and “administered parenterally”as used herein means modes of administration other than enteral andtopical administration, usually by injection, and includes, withoutlimitation, intravenous, intramuscular, intraarterial, intrathecal,intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal,transtracheal, subcutaneous, subcuticular, intraarticulare, subcapsular,subarachnoid, intraspinal and intrasternal injection and infusion.

The phrases “systemic administration,” “administered systemically,”“peripheral administration” and “administered peripherally” as usedherein mean the administration of a compound, drug or other materialother than directly into the central nervous system, such that it entersthe patient's system and, thus, is subject to metabolism and other likeprocesses, for example, subcutaneous administration.

These compounds may be administered to humans and other animals fortherapy by any suitable route of administration, including orally,nasally, as by, for example, a spray, rectally, intravaginally,parenterally, intracisternally and topically, as by powders, ointmentsor drops, including buccally and sublingually.

Regardless of the route of administration selected, the compounds of thepresent invention, which may be used in a suitable hydrated form, and/orthe pharmaceutical compositions of the present invention, are formulatedinto pharmaceutically-acceptable dosage forms by conventional methodsknown to those of skill in the art.

Actual dosage levels of the active ingredients in the pharmaceuticalcompositions of this invention may be varied so as to obtain an amountof the active ingredient which is effective to achieve the desiredtherapeutic response for a particular patient, composition, and mode ofadministration, without being toxic to the patient.

The selected dosage level will depend upon a variety of factorsincluding the activity of the particular compound of the presentinvention employed, or the ester, salt or amide thereof, the route ofadministration, the time of administration, the rate of excretion ormetabolism of the particular compound being employed, the rate andextent of absorption, the duration of the treatment, other drugs,compounds and/or materials used in combination with the particularcompound employed, the age, sex, weight, condition, general health andprior medical history of the patient being treated, and like factorswell known in the medical arts.

A physician or veterinarian having ordinary skill in the art can readilydetermine and prescribe the effective amount of the pharmaceuticalcomposition required. For example, the physician or veterinarian couldstart doses of the compounds of the invention employed in thepharmaceutical composition at levels lower than that required in orderto achieve the desired therapeutic effect and gradually increase thedosage until the desired effect is achieved.

In general, a suitable daily dose of a compound of the invention will bethat amount of the compound which is the lowest dose effective toproduce a therapeutic effect. Such an effective dose will generallydepend upon the factors described above. Generally, oral, intravenous,intracerebroventricular and subcutaneous doses of the compounds of thisinvention for a patient, when used for the indicated analgesic effects,will range from about 0.0001 to about 100 mg per kilogram of body weightper day.

If desired, the effective daily dose of the active compound may beadministered as two, three, four, five, six or more sub-dosesadministered separately at appropriate intervals throughout the day,optionally, in unit dosage forms. Preferred dosing is one administrationper day.

While it is possible for a compound of the present invention to beadministered alone, it is preferable to administer the compound as apharmaceutical formulation (composition).

The compounds according to the invention may be formulated foradministration in any convenient way for use in human or veterinarymedicine, by analogy with other pharmaceuticals.

In another aspect, the present invention provides pharmaceuticallyacceptable compositions which comprise a therapeutically-effectiveamount of one or more of the subject compounds, as described above,formulated together with one or more pharmaceutically acceptablecarriers (additives) and/or diluents. As described in detail below, thepharmaceutical compositions of the present invention may be speciallyformulated for administration in solid or liquid form, including thoseadapted for the following: (1) oral administration, for example,drenches (aqueous or non-aqueous solutions or suspensions), tablets,boluses, powders, granules, pastes for application to the tongue; (2)parenteral administration, for example, by subcutaneous, intramuscularor intravenous injection as, for example, a sterile solution orsuspension; (3) topical application, for example, as a cream, ointmentor spray applied to the skin, lungs, or mucous membranes; or (4)intravaginally or intrarectally, for example, as a pessary, cream orfoam; (5) sublingually or buccally; (6) ocularly; (7) transdermally; or(8) nasally.

The term “treatment” is intended to encompass also prophylaxis, therapyand cure.

The patient receiving this treatment is any animal in need, includingprimates, in particular humans, and other mammals such as equines,cattle, swine and sheep; and poultry and pets in general.

Microemulsification technology can improve bioavailability of somelipophilic (water insoluble) pharmaceutical agents. Examples includeTrimetrine (Dordunoo, S. K., et al., Drug Development and IndustrialPharmacy, 17(12), 1685-1713, 1991 and REV 5901 (Sheen, P. C., et al., JPharm Sci 80(7), 712-714, 1991). Among other things, microemulsificationprovides enhanced bioavailability by preferentially directing absorptionto the lymphatic system instead of the circulatory system, which therebybypasses the liver, and prevents destruction of the compounds in thehepatobiliary circulation.

While all suitable amphiphilic carriers are contemplated, the presentlypreferred carriers are generally those that haveGenerally-Recognized-as-Safe (GRAS) status, and that can both solubilizethe compound of the present invention and microemulsify it at a laterstage when the solution comes into a contact with a complex water phase(such as one found in human gastrointestinal tract). Usually,amphiphilic ingredients that satisfy these requirements have HLB(hydrophilic to lipophilic balance) values of 2-20, and their structurescontain straight chain aliphatic radicals in the range of C-6 to C-20.Examples are polyethylene-glycolized fatty glycerides and polyethyleneglycols.

Commercially available amphiphilic carriers are particularlycontemplated, including Gelucire-series, Labrafil, Labrasol, orLauroglycol (all manufactured and distributed by Gattefosse Corporation,Saint Priest, France), PEG-mono-oleate, PEG-di-oleate, PEG-mono-laurateand di-laurate, Lecithin, Polysorbate 80, etc (produced and distributedby a number of companies in USA and worldwide).

Hydrophilic polymers suitable for use in the present invention are thosewhich are readily water-soluble, can be covalently attached to avesicle-forming lipid, and which are tolerated in vivo without toxiceffects (i.e., are biocompatible). Suitable polymers includepolyethylene glycol (PEG), polylactic (also termed polylactide),polyglycolic acid (also termed polyglycolide), a polylactic-polyglycolicacid copolymer, and polyvinyl alcohol. Preferred polymers are thosehaving a molecular weight of from about 100 or 120 daltons up to about5,000 or 10,000 daltons, and more preferably from about 300 daltons toabout 5,000 daltons. In a particularly preferred embodiment, the polymeris polyethyleneglycol having a molecular weight of from about 100 toabout 5,000 daltons, and more preferably having a molecular weight offrom about 300 to about 5,000 daltons. In a particularly preferredembodiment, the polymer is polyethyleneglycol of 750 daltons (PEG(750)).Polymers may also be defined by the number of monomers therein; apreferred embodiment of the present invention utilizes polymers of atleast about three monomers, such PEG polymers consisting of threemonomers (approximately 150 daltons).

Other hydrophilic polymers which may be suitable for use in the presentinvention include polyvinylpyrrolidone, polymethoxazoline,polyethyloxazoline, polyhydroxypropyl methacrylamide,polymethacrylamide, polydimethylacrylamide, and derivatized cellulosessuch as hydroxymethylcellulose or hydroxyethylcellulose.

In certain embodiments, a formulation of the present invention comprisesa biocompatible polymer selected from the group consisting ofpolyamides, polycarbonates, polyalkylenes, polymers of acrylic andmethacrylic esters, polyvinyl polymers, polyglycolides, polysiloxanes,polyurethanes and co-polymers thereof, celluloses, polypropylene,polyethylenes, polystyrene, polymers of lactic acid and glycolic acid,polyanhydrides, poly(ortho)esters, poly(butic acid), poly(valeric acid),poly(lactide-co-caprolactone), polysaccharides, proteins, polyhyaluronicacids, polycyanoacrylates, and blends, mixtures, or copolymers thereof.

Cyclodextrins are cyclic oligosaccharides, consisting of 6, 7 or 8glucose units, designated by the Greek letter alpha, beta or gamma,respectively. Cyclodextrins with fewer than six glucose units are notknown to exist. The glucose units are linked by alpha-1,4-glucosidicbonds. As a consequence of the chair conformation of the sugar units,all secondary hydroxyl groups (at C-2, C-3) are located on one side ofthe ring, while all the primary hydroxyl groups at C-6 are situated onthe other side. As a result, the external faces are hydrophilic, makingthe cyclodextrins water-soluble. In contrast, the cavities of thecyclodextrins are hydrophobic, since they are lined by the hydrogen ofatoms C-3 and C-5, and by ether-like oxygens. These matrices allowcomplexation with a variety of relatively hydrophobic compounds,including, for instance, steroid compounds such as 17-beta-estradiol(see, e.g., van Uden et al. Plant Cell Tiss. Org. Cult. 38:1-3-113(1994)). The complexation takes place by Van der Waals interactions andby hydrogen bond formation. For a general review of the chemistry ofcyclodextrins, see, Wenz, Agnew. Chem. Int. Ed. Engl., 33:803-822(1994).

The physico-chemical properties of the cyclodextrin derivatives dependstrongly on the kind and the degree of substitution. For example, theirsolubility in water ranges from insoluble (e.g.,triacetyl-beta-cyclodextrin) to 147% soluble (w/v)(G-2-beta-cyclodextrin). In addition, they are soluble in many organicsolvents. The properties of the cyclodextrins enable the control oversolubility of various formulation components by increasing or decreasingtheir solubility.

Numerous cyclodextrins and methods for their preparation have beendescribed. For example, Parmeter (I), et al. (U.S. Pat. No. 3,453,259)and Gramera, et al. (U.S. Pat. No. 3,459,731) described electroneutralcyclodextrins. Other derivatives include cyclodextrins with cationicproperties [Parmeter (II), U.S. Pat. No. 3,453,257], insolublecrosslinked cyclodextrins (Solms, U.S. Pat. No. 3,420,788), andcyclodextrins with anionic properties [Parmeter (III), U.S. Pat. No.3,426,011]. Among the cyclodextrin derivatives with anionic properties,carboxylic acids, phosphorous acids, phosphinous acids, phosphonicacids, phosphoric acids, thiophosphonic acids, thiosulphinic acids, andsulfonic acids have been appended to the parent cyclodextrin [see,Parmeter (III), supra]. Furthermore, sulfoalkyl ether cyclodextrinderivatives have been described by Stella, et al. (U.S. Pat. No.5,134,127).

Liposomes consist of at least one lipid bilayer membrane enclosing anaqueous internal compartment. Liposomes may be characterized by membranetype and by size. Small unilamellar vesicles (SUVs) have a singlemembrane and typically range between 0.02 and 0.05 μm in diameter; largeunilamellar vesicles (LUVS) are typically larger than 0.05 μmOligolamellar large vesicles and multilamellar vesicles have multiple,usually concentric, membrane layers and are typically larger than 0.1μm. Liposomes with several nonconcentric membranes, i.e., severalsmaller vesicles contained within a larger vesicle, are termedmultivesicular vesicles.

One aspect of the present invention relates to formulations comprisingliposomes containing a compound of the present invention, where theliposome membrane is formulated to provide a liposome with increasedcarrying capacity. Alternatively or in addition, the compound of thepresent invention may be contained within, or adsorbed onto, theliposome bilayer of the liposome. The compound of the present inventionmay be aggregated with a lipid surfactant and carried within theliposome's internal space; in these cases, the liposome membrane isformulated to resist the disruptive effects of the activeagent-surfactant aggregate.

According to one embodiment of the present invention, the lipid bilayerof a liposome contains lipids derivatized with polyethylene glycol(PEG), such that the PEG chains extend from the inner surface of thelipid bilayer into the interior space encapsulated by the liposome, andextend from the exterior of the lipid bilayer into the surroundingenvironment.

Active agents contained within liposomes of the present invention are insolubilized form. Aggregates of surfactant and active agent (such asemulsions or micelles containing the active agent of interest) may beentrapped within the interior space of liposomes according to thepresent invention. A surfactant acts to disperse and solubilize theactive agent, and may be selected from any suitable aliphatic,cycloaliphatic or aromatic surfactant, including but not limited tobiocompatible lysophosphatidylcholines (LPCs) of varying chain lengths(for example, from about C.sub.14 to about C.sub.20).Polymer-derivatized lipids such as PEG-lipids may also be utilized formicelle formation as they will act to inhibit micelle/membrane fusion,and as the addition of a polymer to surfactant molecules decreases theCMC of the surfactant and aids in micelle formation. Preferred aresurfactants with CMCs in the micromolar range; higher CMC surfactantsmay be utilized to prepare micelles entrapped within liposomes of thepresent invention, however, micelle surfactant monomers could affectliposome bilayer stability and would be a factor in designing a liposomeof a desired stability.

Liposomes according to the present invention may be prepared by any of avariety of techniques that are known in the art. See, e.g., U.S. Pat.No. 4,235,871; Published PCT applications WO 96/14057; New RRC,Liposomes: A practical approach, IRL Press, Oxford (1990), pages 33-104;Lasic DD, Liposomes from physics to applications, Elsevier SciencePublishers BV, Amsterdam, 1993.

For example, liposomes of the present invention may be prepared bydiffusing a lipid derivatized with a hydrophilic polymer into preformedliposomes, such as by exposing preformed liposomes to micelles composedof lipid-grafted polymers, at lipid concentrations corresponding to thefinal mole percent of derivatized lipid which is desired in theliposome. Liposomes containing a hydrophilic polymer can also be formedby homogenization, lipid-field hydration, or extrusion techniques, asare known in the art.

In one aspect of the present invention, the liposomes are prepared tohave substantially homogeneous sizes in a selected size range. Oneeffective sizing method involves extruding an aqueous suspension of theliposomes through a series of polycarbonate membranes having a selecteduniform pore size; the pore size of the membrane will correspond roughlywith the largest sizes of liposomes produced by extrusion through thatmembrane. See e.g., U.S. Pat. No. 4,737,323 (Apr. 12, 1988).

The release characteristics of a formulation of the present inventiondepend on the encapsulating material, the concentration of encapsulateddrug, and the presence of release modifiers. For example, release can bemanipulated to be pH dependent, for example, using a pH sensitivecoating that releases only at a low pH, as in the stomach, or a higherpH, as in the intestine. An enteric coating can be used to preventrelease from occurring until after passage through the stomach. Multiplecoatings or mixtures of cyanamide encapsulated in different materialscan be used to obtain an initial release in the stomach, followed bylater release in the intestine. Release can also be manipulated byinclusion of salts or pore forming agents, which can increase wateruptake or release of drug by diffusion from the capsule. Excipientswhich modify the solubility of the drug can also be used to control therelease rate. Agents which enhance degradation of the matrix or releasefrom the matrix can also be incorporated. They can be added to the drug,added as a separate phase (i.e., as particulates), or can beco-dissolved in the polymer phase depending on the compound. In allcases the amount should be between 0.1 and thirty percent (w/w polymer).Types of degradation enhancers include inorganic salts such as ammoniumsulfate and ammonium chloride, organic acids such as citric acid,benzoic acid, and ascorbic acid, inorganic bases such as sodiumcarbonate, potassium carbonate, calcium carbonate, zinc carbonate, andzinc hydroxide, and organic bases such as protamine sulfate, spermine,choline, ethanolamine, diethanolamine, and triethanolamine andsurfactants such as Tween® and Pluronic®. Pore forming agents which addmicrostructure to the matrices (i.e., water soluble compounds such asinorganic salts and sugars) are added as particulates. The range shouldbe between one and thirty percent (w/w polymer).

Uptake can also be manipulated by altering residence time of theparticles in the gut. This can be achieved, for example, by coating theparticle with, or selecting as the encapsulating material, a mucosaladhesive polymer. Examples include most polymers with free carboxylgroups, such as chitosan, celluloses, and especially polyacrylates (asused herein, polyacrylates refers to polymers including acrylate groupsand modified acrylate groups such as cyanoacrylates and methacrylates).

Pharmaceutical Combinations

The invention especially relates to the use of a compound of the formula(I) (or a pharmaceutical composition comprising a compound of theformula (I) in the treatment of one or more of the diseases mentionedherein; wherein the response to treatment is beneficial as demonstrated,for example, by the partial or complete removal of one or more of thesymptoms of the disease up to complete cure or remission.

Philadelphia chromosome positive (Ph+) ALL accounts for 15-30% of adultALL and up to 5% of pediatric ALL (Faderl S, Garcia-MAnero G, Thomas D,et al. Philadelphia Chromosome Positive Acute LymphoblasticLeukemia-Current Concepts and Future Perspectives. Rev Clin Exp Hematol2002; 6:142-160). Pediatric Ph+ ALL is characterized by an older age(median 9-10 years versus approximately 4 years for all ALL patients)and higher WBC counts at diagnosis. In both adults and children, Ph+ ALLis characterized by a reciprocal translocation between chromosomes 9 and22 (t(9; 22)(q34; q11)) resulting in fusion of the BCR gene onchromosome 22 with ABL gene sequences translocated from chromosome 9,resulting in expression of the BCR-ABL1 protein. There are 2 primaryvariants of BCR-ABL1, p190BCR-ABL1, detectable in approximately 85% ofPh+ ALL patients, and p210 BCR-ABL1, typical of CML, identified inapproximately 15% of Ph+ ALL patients (Dombret H, Galbert J, Boiron J,et al. Outcome of Treatment in Adults with Philadelphiachromosome-posititve acute lymphoblastic leukemia—Results of theprospective multicenter LALA-94 trial. Blood 2002; 100:2357-2366; FaderlS, Garcia-MAnero G, Thomas D, et al. Philadelphia Chromosome PositiveAcute Lymphoblastic Leukemia—Current Concepts and Future Perspectives.Rev Clin Exp Hematol 2002; 6:142-160).

The treatment of ALL is based on each patient's risk classification,with increasingly intensive treatment for patients who are at higherrisk of relapse; this strategy maximizes remission rates while limitingunnecessary toxicities. Progress has been incremental, from theintroduction of combination chemotherapy and treatment forpre-symptomatic central nervous system leukemia to newer, intensivetreatment regimens for patients at high risk for relapse (C. H. Pui andW. E. Evans. Acute Lymphoblastic Leukemia New Engl J Med 1998;339:605-615). Prior to the development of imatinib, Ph+ ALL patientswere treated with intensive chemotherapy followed by hematopoietic stemcell transplant (HSCT), ideally with a matched related donor, as thiswas shown to result in improved EFS versus either HSCT with other donorsor chemotherapy alone. Overall, and in contrast to the majority ofpediatric patients with ALL, patients with Ph+ ALL have had a direprognosis with low rates of event free survival (EFS) (Arico M,Valsecchi M G, Camitta B, Schrappe M, Chessells J, Baruchel A, Gaynon P,Silverman L, Janka-Schaub G, Kamps W, et al. New Engl J Med 2000;342:998-1006).

A compound of formula (I) can also be used in combination with otherantineoplastic compounds. Such compounds include, but are not limited toribonucleotide reductase inhibitors, topoisomerase I inhibitors;topoisomerase II inhibitors; microtubule active compounds; alkylatingcompounds; histone deacetylase inhibitors; mTOR inhibitors, such asRAD001; antineoplastic antimetabolites; platin compounds; compoundstargeting/decreasing a protein or lipid kinase activity methionineaminopeptidase inhibitors; biological response modifiers; inhibitors ofRas oncogenic isoforms; telomerase inhibitors; proteasome inhibitors;compounds used in the treatment of hematologic malignancies, such asFLUDARABINE; compounds which target, decrease or inhibit the activity ofPKC, such as midostaurin; HSP90 inhibitors such as 17-AAG(17-allylaminogeldanamycin, NSC330507), 17-DMAG(17-dimethylaminoethylamino-17-demethoxy-geldanamycin, NSC707545),IPI-504, CNF1010, CNF2024, CNF1010 from Conforma Therapeutics, HSP990and AUY922; temozolomide (TEMODAL®); kinesin spindle protein inhibitors,such as SB715992 or SB743921 from GlaxoSmithKline, orpentamidine/chlorpromazine from CombinatoRx; PI3K inhibitors, such asBEZ235, BKM120 or BYL719; MEK inhibitors such as ARRY142886 from ArrayPioPharma, AZD6244 from AstraZeneca, PD181461 from Pfizer, leucovorin,EDG binders, antileukemia compounds, S-adenosylmethionine decarboxylaseinhibitors, antiproliferative antibodies or other chemotherapeuticcompounds. Further, alternatively or in addition they may be used incombination with ionizing radiation

The term “ribonucleotide reductase inhibitors” refers to pyrimidine orpurine nucleoside analogues including, but not limited to, fludarabineand/or cytosine arabinoside (ara-C), 6-thioguanine, 5-fluorouracil,cladribine, 6-mercaptopurine (especially in combination with ara-Cagainst ALL), clofarabine, nelarabine (a prodrug of9-β-arabinofuranosylguanine, ara-G), pentostatin, hydroxyurea or2-hydroxy-1H-isoindole-1,3-dione derivatives (Nandy et al., ActaOncologica 1994; 33:953-961.

The term “topoisomerase I inhibitor” as used herein includes, but is notlimited to topotecan, gimatecan, irinotecan, camptothecian and itsanalogues, 9-nitrocamptothecin and the macromolecular camptothecinconjugate PNU-166148 (compound A1 in W099/17804). Irinotecan can beadministered, e.g. in the form as it is marketed, e.g. under thetrademark CAMPTOSAR. Topotecan can be administered, e.g., in the form asit is marketed, e.g. under the trademark HYCAMTIN.

The term “topoisomerase II inhibitor” as used herein includes, but isnot limited to the anthracyclines such as doxorubicin (includingliposomal formulation, e.g. CAELYX), daunorubicin, epirubicin,idarubicin and nemorubicin, the anthraquinones mitoxantrone andlosoxantrone, and the podophillotoxines etoposide and teniposide.Etoposide can be administered, e.g. in the form as it is marketed, e.g.under the trademark ETOPOPHOS. Teniposide can be administered, e.g. inthe form as it is marketed, e.g. under the trademark VM 26-BRISTOL.Doxorubicin can be administered, e.g. in the form as it is marketed,e.g. under the trademark ADRIBLASTIN or ADRIAMYCIN. Epirubicin can beadministered, in the form as it is marketed. under the trademarkFARMORUBICIN. Idarubicin can be administered, e.g. in the form as it ismarketed, e.g. under the trademark ZAVEDOS. Mitoxantrone can beadministered, e.g. in the form as it is marketed, e.g. under thetrademark NOVANTRON.

The term “microtubule active compound” relates to microtubulestabilizing, microtubule destabilizing compounds and microtublinpolymerization inhibitors including, but not limited to taxanes, e.g.paclitaxel and docetaxel, vinca alkaloids, e.g., vinblastine, especiallyvinblastine sulfate, vincristine especially vincristine sulfate, andvinorelbine, discodermolides, cochicine and epothilones and derivativesthereof, e.g. epothilone B or D or derivatives thereof. Paclitaxel maybe administered e.g. in the form as it is marketed, e.g. TAXOL.Docetaxel can be administered, e.g., in the form as it is marketed, e.g.under the trademark TAXOTERE. Vinblastine sulfate can be administered,e.g., in the form as it is marketed, e.g. under the trademark VINBLASTINR.P. Vincristine sulfate can be administered, e.g., in the form as it ismarketed, e.g. under the trademark FARMISTIN. Discodermolide can beobtained, e.g., as disclosed in U.S. Pat. No. 5,010,099. Also includedare Epothilone derivatives which are disclosed in WO 98/10121, U.S. Pat.No. 6,194,181, WO 98/25929, WO 98/08849, WO 99/43653, WO 98/22461 and WO00/31247. Especially preferred are Epothilone A and/or B.

The term “alkylating compound” as used herein includes, but is notlimited to, cyclophosphamide, ifosfamide, melphalan or nitrosourea (BCNUor Gliadel). Cyclophosphamide can be administered, e.g., in the form asit is marketed, e.g. under the trademark CYCLOSTIN. Ifosfamide can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark HOLOXAN.

The term “histone deacetylase inhibitors” or “HDAC inhibitors” relatesto compounds which inhibit the histone deacetylase and which possessantiproliferative activity. This includes compounds such as LDH589disclosed in WO 02/22577, especiallyN-hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide,N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamideand pharmaceutically acceptable salts thereof. It further especiallyincludes Suberoylanilide hydroxamic acid (SAHA).

The term “antineoplastic antimetabolite” includes, but is not limitedto, 5-fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylatingcompounds, such as 5-azacytidine and decitabine, methotrexate andedatrexate, and folic acid antagonists such as pemetrexed. Capecitabinecan be administered, e.g., in the form as it is marketed, e.g. under thetrademark XELODA. Gemcitabine can be administered, e.g., in the form asit is marketed, e.g. under the trademark GEMZAR.

The term “platin compound” as used herein includes, but is not limitedto, carboplatin, cis-platin, cisplatinum and oxaliplatin. Carboplatincan be administered, e.g., in the form as it is marketed, e.g. under thetrademark CARBOPLAT. Oxaliplatin can be administered, e.g., in the formas it is marketed, e.g. under the trademark ELOXATIN.

The term “compounds targeting/decreasing a protein or lipid kinaseactivity”; or a “protein or lipid phosphatase activity” as used hereinincludes, but is not limited to, protein tyrosine kinase and/or serineand/or threonine kinase inhibitors or lipid kinase inhibitors, forexample:

a) compounds targeting, decreasing or inhibiting the activity of membersof the ABL1 family, their gene-fusion products (e.g. BCR-ABL1 kinase)and mutants, such as compounds which target decrease or inhibit theactivity of ABL1 family members and their gene fusion products, e.g.imatinib, nilotinib, dasatinib, bosutinib, ponatinib, bafetinib,PD180970, AG957, NSC 680410 and PD173955;

b) compounds targeting, decreasing or inhibiting the activity of membersof the protein kinase C (PKC) and Raf family of serine/threoninekinases, members of the MEK, SRC, JAK, FAK, PDK1, PKB/Akt, and Ras/MAPKfamily members, and/or members of the cyclin-dependent kinase family(CDK) and are especially those staurosporine derivatives disclosed inU.S. Pat. No. 5,093,330, e.g. midostaurin; examples of further compoundsinclude e.g. UCN-01, safingol, BAY 43-9006, Bryostatin 1, Perifosine;Ilmofosine; RO 318220 and RO 320432; GO 6976; Isis 3521;LY333531/LY379196; isochinoline compounds such as those disclosed in WO00/09495; FTIs; BEZ235 (a P13K inhibitor) or AT7519 (CDK inhibitor);

The term “mTOR inhibitors” relates to compounds which inhibit themammalian target of rapamycin (mTOR) and which possess antiproliferativeactivity such as sirolimus (Rapamune®), everolimus (Certican™), CCI-779and ABT578.

The term “biological response modifier” as used herein refers to alymphokine or interferons, e.g. interferon γ.

The term “inhibitor of Ras oncogenic isoforms”, e.g. H-Ras, K-Ras, orN-Ras, as used herein refers to compounds which target, decrease orinhibit the oncogenic activity of Ras e.g. a “farnesyl transferaseinhibitor” e.g. L-744832, DK8G557 or R115777 (Zarnestra).

The term “telomerase inhibitor” as used herein refers to compounds whichtarget, decrease or inhibit the activity of telomerase. Compounds whichtarget, decrease or inhibit the activity of telomerase are especiallycompounds which inhibit the telomerase receptor, e.g. telomestatin.

The term “methionine aminopeptidase inhibitor” as used herein refers tocompounds which target, decrease or inhibit the activity of methionineaminopeptidase. Compounds which target, decrease or inhibit the activityof methionine aminopeptidase are e.g. bengamide or a derivative thereof.

The term “proteasome inhibitor” as used herein refers to compounds whichtarget, decrease or inhibit the activity of the proteasome. Compoundswhich target, decrease or inhibit the activity of the proteasome includee.g. Bortezomid (Velcade™) and MLN 341.

The term “HSP90 inhibitors” as used herein includes, but is not limitedto, compounds targeting, decreasing or inhibiting the intrinsic ATPaseactivity of HSP90; degrading, targeting, decreasing or inhibiting theHSP90 client proteins via the ubiquitin proteosome pathway. Compoundstargeting, decreasing or inhibiting the intrinsic ATPase activity ofHSP90 are especially compounds, proteins or antibodies which inhibit theATPase activity of HSP90e.g., 17-allylamino,17-demethoxygeldanamycin(17AAG), a geldanamycin derivative; other geldanamycin relatedcompounds; radicicol and HDAC inhibitors. Example HSP90 inhibitors areHSP990 and AUY922.

For the treatment of acute myeloid leukemia (AML), compounds of formula(I) can be used in combination with standard leukemia therapies,especially in combination with therapies used for the treatment of AML.In particular, compounds of formula (I) can be administered incombination with, e.g., farnesyl transferase inhibitors and/or otherdrugs useful for the treatment of AML, such as Daunorubicin, Adriamycin,Ara-C, VP-16, Teniposide, Mitoxantrone, Idarubicin, Carboplatinum andPKC412.

Compounds which target, decrease or inhibit activity of histonedeacetylase (HDAC) inhibitors such as sodium butyrate andsuberoylanilide hydroxamic acid (SAHA) inhibit the activity of theenzymes known as histone deacetylases. Specific HDAC inhibitors includeMS275, SAHA, FK228 (formerly FR901228), Trichostatin A and compoundsdisclosed in U.S. Pat. No. 6,552,065, in particular,N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]-methyl]phenyl]-2E-2-propenamide,or a pharmaceutically acceptable salt thereof andN-hydroxy-3-[4-[(2-hydroxyethyl){2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide,or a pharmaceutically acceptable salt thereof, especially the lactatesalt.

Tumor cell damaging approaches refer to approaches such as ionizingradiation. The term “ionizing radiation” referred to above andhereinafter means ionizing radiation that occurs as eitherelectromagnetic rays (such as X-rays and gamma rays) or particles (suchas alpha and beta particles). Ionizing radiation is provided in, but notlimited to, radiation therapy and is known in the art. See Hellman,Principles of Radiation Therapy, Cancer, in Principles and Practice ofOncology, Devita et al., Eds., 4^(th) Edition, Vol. 1, pp. 248-275(1993).

The term “S-adenosylmethionine decarboxylase inhibitors” as used hereinincludes, but is not limited to the compounds disclosed in U.S. Pat. No.5,461,076.

“Other chemotherapeutic compounds” include, but are not limited to,plant alkaloids, hormonal compounds and antagonists; biological responsemodifiers, preferably lymphokines or interferons; antisenseoligonucleotides or oligonucleotide derivatives; shRNA or siRNA; ormiscellaneous compounds or compounds with other or unknown mechanism ofaction.

The structure of the active compounds identified by code nos., genericor trade names may be taken from the actual edition of the standardcompendium “The Merck Index” or from databases, e.g. PatentsInternational (e.g. IMS World Publications).

None of the quotations of references made within the present disclosureis to be understood as an admission that the references cited are priorart that would negatively affect the patentability of the presentinvention.

Processes for Making Compounds of the Invention

The present invention also includes processes for the preparation ofcompounds of the invention. In the reactions described, it can benecessary to protect reactive functional groups, for example hydroxy,amino, imino, thio or carboxy groups, where these are desired in thefinal product, to avoid their unwanted participation in the reactions.Conventional protecting groups can be used in accordance with standardpractice, for example, see T.W. Greene and P. G. M. Wuts in “ProtectiveGroups in Organic Chemistry”, John Wiley and Sons, 1991.

Where temperatures are given hereinbefore or hereinafter, “about” has tobe added, as minor deviations from the numeric values given, e.g.variations of ±10%, are tolerable. All reactions may take place in thepresence of one or more diluents and/or solvents. The starting materialsmay be used in equimolar amounts; alternatively, a compound may be usedin excess, e.g. to function as a solvent or to shift equilibrium or togenerally accelerate reaction rates. Reaction aids, such as acids, basesor catalysts may be added in suitable amounts, as known in the field,required by a reaction and in line with generally known procedures.

Compounds of formula (I) can be prepared by proceeding as in thefollowing Reaction Scheme I:

in which Y, Y₁, R₁, R₂, R₃ and R₄ are as defined for formula (I) in theSummary of the Invention and X₁ and X₂ represent halogen atoms, X₁ canbe selected from chloro, bromo, or iodo and X₂ can be selected fromchloro or fluoro.

Step a: A compound of formula (4) can be prepared by reacting the acidchloride from a compound of formula (2) with a compound of formula (3)in the presence of a suitable solvent (for example tetrahydrofuran, orthe like), and an organic base (for example diisopropylethylamine, orthe like). The reaction takes place from about 0° C. to about roomtemperature and can take up to about 2 hours to complete.

The acid chloride of a compound of formula (2) can be prepared with achlorinating agent (for example thionyl chloride, or oxalyl chloride, orthe like) in the presence of a catalyst (for example dimethylformamide,or the like) and a suitable solvent (for example toluene, or the like).The reaction takes place at about room temperature or by heating toabout 85° C. and can take up to about 2 hours to complete.

Step b: A compound of formula (5) can be prepared by reacting a compoundof formula (4) with R₂—H wherein R₂ is as defined in the Summary of theInvention, in the presence of a suitable solvent (for example2-propanol, or dimethyl sulfoxide, or the like), and a suitable organicbase (for example diisopropylethylamine, or triethylamine, or the like).The reaction takes place at about 90° C. to about 140° C. and can takefrom about 30 minutes to about 72 hours to complete.

Step c: A compound of formula (6) can be prepared by reacting a compoundof formula (4), X₁ being preferably bromo or iodo, with R₁—Z₁, whereinR₁ is as defined herein, Z₁ being preferably a boronic acid or ester(Suzuki reaction), in the presence of a suitable solvent (for exampledimethoxyethane, or a mixture of dimethoxyethane and water, or thelike), a suitable inorganic base (for example sodium carbonate, or thelike), and a palladium catalyst (for examplebis(triphenylphosphine)palladium(II) dichloride, or1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloridedichloromethane complex, or tetrakis(triphenylphosphine)palladium(0), orthe like) and optionally a cosolvent (for example, ethanol, or the like.The reaction takes place from about 80° C. to about 130° C. and can takefrom about 20 minutes to about 18 hours to complete.

Alternatively, step c can occur by reacting a compound of formula (4),X₁ being preferably bromo or iodo, with R₁—Z₂, wherein R₁ is as definedherein, Z₂ being preferably a trialkylstannyl reagent (Stille reaction),in the presence of a suitable solvent (for example dimethyl sulfoxide,or the like), and a palladium catalyst (for exampletetrakis(triphenylphosphine)palladium(0). The reaction takes place atabout 140° C. and can take up to about 24 hours to complete.

Step d: A compound of formula (I) can be prepared by reacting a compoundof formula (5), X₁ being preferably bromo or iodo, with R₁—Z₁, whereinR₁ is as defined herein, Z₁ being preferably a boronic acid or ester(Suzuki reaction), in the presence of a suitable solvent (for exampledimethoxyethane, or a mixture of dimethoxyethane and water, or thelike), a inorganic base (for example sodium carbonate, or the like), anda palladium catalyst (for example bis(triphenylphosphine)palladium(II)dichloride, or1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloridedichloromethane complex, or tetrakis(triphenylphosphine)palladium(0), orthe like) and optionally a cosolvent (for example, ethanol, or thelike). The reaction takes place at about 80-130° C. and can take up toabout 20 minutes to 2 hours to complete.

Step e: A compound of formula (I) can be prepared by reacting a compoundof formula (6) with R₂—H wherein R₂ is as defined herein, in thepresence of a suitable solvent (for example 2-propanol, or dimethylsulfoxide, or the like), an organic base (for examplediisopropylethylamine, or triethylamine, or the like). The reactiontakes place at about 90-140° C. and can take up to about 30 minutes to72 hours to complete.

Compounds of formula (I) can be prepared by proceeding as in thefollowing Reaction Scheme II:

in which Y, Y₁, R₁, R₂, R₃ and R₄ are as defined for formula (I) in theSummary of the Invention and X₁ and X₂ represent halogen atoms, X₁ inparticular chloro, bromo, or iodo, X₂ in particular chloro or fluoro andAlk is low alkyl chain in particular methyl.

Step f: A compound of formula (8) can be prepared by reacting a compoundof formula (7) with R₂—H wherein R₂ is as defined herein, in analogy toStep b

Step g: A compound of formula (9) can be prepared by reacting a compoundof formula (8), X₁ being preferably bromo or iodo, with R₁—Z₁, where R₁is as defined herein, Z₁ being preferably a boronic acid or ester(Suzuki reaction), in analogy to Step d.

Step h: A compound of formula (10) can be prepared by hydrolysis of theester of a compound of formula (9) in the presence of a suitable solvent(for example water, or the like), an inorganic base (for example sodiumhydroxide, or the like). The reaction takes place at room temperatureand can take up to about 2 hours complete.

Step i: A compound of formula (I) can be prepared by reacting a compoundof (10) with a compound of formula (3) in the presence of a couplingreagent (such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride and hydroxybenzotriazole, or the like), a suitable base(such as N-methylmorpholine, diisopropylethylamine, or the like) and asuitable solvent (such as dichloro methane, dimethylformamide, or thelike). The reaction takes place at room temperature and can take up toabout 12 hours to complete.

Compounds of formula (I) can be prepared by proceeding as in thefollowing Reaction Scheme III:

in which Y, Y₁, R₁, R₂, R₃ and R₄ are as defined for formula (I) in theSummary of the Invention and X₁ and X₂ represent halogen atoms, X₁ inparticular chloro, bromo, or iodo, X₂ in particular chloro or fluoro.

Step j: A compound of formula (11) can be prepared by reacting acompound of formula (5), X₁ being preferably bromo, withbis(pinacolato)diboron, in the presence of a suitable solvent (forexample dioxane, or the like), an inorganic base (for exampletripotassium carbonate, or the like), and a palladium catalyst (forexample bis(triphenylphosphine)palladium(II) dichloride, or the like).The reaction takes place at about 50-65° C. and can take up to 32 hoursto complete.

Step k: A compound of formula (I) can be prepared by reacting a compoundof formula (11) with R1-X₃, X₃ being preferably bromo, in the presenceof a suitable solvent (for example dimethoxyethane, or the like), ainorganic base (for example sodium carbonate, or the like), and apalladium catalyst (for example2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl-palladium diacetate, orthe like). The reaction takes place at about 90-125° C. and can take up20 minutes to 16 hours to complete.

Compounds of formula (I) can be prepared by proceeding as in thefollowing Reaction Scheme IV:

in which Y, Y₁, R₂, R₃ and R₄ are as defined for formula (I) in theSummary of the Invention, and X₃ is a halogen, in particular chlorineand R a lower alkyl, in particular methyl.

Step 1: A compound of formula (Im) can be prepared by reacting acompound of formula (12) by reacting with an alkyl boroxine (for examplemethyl-boroxine, or the like) in the presence of a suitable solvent (forexample dioxane, or the like), an inorganic base (for example potassiumcarbonate, or the like), and a palladium catalyst (for exampletetrakis(triphenylphosphine)palladium(0), or the like). The reactiontakes place at about 80° C. and can take up to 2 hours to complete.

Detailed examples of the synthesis of compounds of formula (I) can befound in the Examples, infra.

Additional Processes for Making Compounds of the Invention

A compound of the invention can be prepared as a pharmaceuticallyacceptable acid addition salt by reacting the free base form of thecompound with a pharmaceutically acceptable inorganic or organic acid.Alternatively, a pharmaceutically acceptable base addition salt of acompound of the invention can be prepared by reacting the free acid formof the compound with a pharmaceutically acceptable inorganic or organicbase.

Compounds of the formula (I) can also be modified by appendingappropriate functionalities to enhance selective biological properties.Modifications of this kind are known in the art and include those thatincrease penetration into a given biological system (e.g. blood,lymphatic system, central nervous system, testis), increasebioavailability, increase solubility to allow parenteral administration(e.g. injection, infusion), alter metabolism and/or alter the rate ofsecretion. Examples of this type of modifications include but are notlimited to esterification, e.g. with polyethylene glycols,derivatisation with pivaloyloxy or fatty acid substituents, conversionto carbamates, hydroxylation of aromatic rings and heteroatomsubstitution in aromatic rings. Whereever compounds of the formula (I),and/or N-oxides, tautomers and/or (preferably pharmaceuticallyacceptable) salts thereof are mentioned, this comprises such modifiedformulae, while preferably the molecules of the formula (I), theirN-oxides, their tautomers and/or their salts are meant.

Alternatively, the salt forms of the compounds of the invention can beprepared using salts of the starting materials or intermediates. In viewof the close relationship between the novel compounds of the formula (I)in free form and those in the form of their salts, including those saltsthat can be used as intermediates, for example in the purification oridentification of the novel compounds, any reference to the compounds ora compound of the formula (I) hereinbefore and hereinafter is to beunderstood as referring to the compound in free form and/or also to oneor more salts thereof, as appropriate and expedient, as well as to oneor more solvates, e.g. hydrates.

Salts are formed, for example, as acid addition salts, preferably withorganic or inorganic acids, from compounds of formula (I) with a basicnitrogen atom, especially the pharmaceutically acceptable salts.Suitable inorganic acids are, for example, halogen acids, such ashydrochloric acid, sulfuric acid, or phosphoric acid. Suitable organicacids are, for example, carboxylic, phosphonic, sulfonic or sulfamicacids, for example acetic acid, propionic acid, octanoic acid, decanoicacid, dodecanoic acid, glycolic acid, lactic acid, fumaric acid,succinic acid, malonic acid, adipic acid, pimelic acid, suberic acid,azelaic acid, malic acid, tartaric acid, citric acid, amino acids, suchas glutamic acid or aspartic acid, maleic acid, hydroxymaleic acid,methylmaleic acid, cyclohexanecarboxylic acid, adamantanecarboxylicacid, benzoic acid, salicylic acid, 4-aminosalicylic acid, phthalicacid, phenylacetic acid, mandelic acid, cinnamic acid, methane- orethane-sulfonic acid, 2-hydroxyethanesulfonic acid,ethane-1,2-disulfonic acid, benzenesulfonic acid, 4-toluenesulfonicacid, 2-naphthalenesulfonic acid, 1,5-naphthalene-disulfonic acid, 2- or3-methylbenzenesulfonic acid, methylsulfuric acid, ethylsulfuric acid,dodecylsulfuric acid, N-cyclohexylsulfamic acid, N-methyl-, N-ethyl- orN-propyl-sulfamic acid, or other organic protonic acids, such asascorbic acid. Salts can usually be converted to free compounds, e.g. bytreating with suitable basic compounds, for example with alkali metalcarbonates, alkali metal hydrogencarbonates, or alkali metal hydroxides,typically potassium carbonate or sodium hydroxide.

For isolation or purification purposes it is also possible to usepharmaceutically unacceptable salts, for example picrates orperchlorates. For therapeutic use, only pharmaceutically acceptablesalts or free compounds are employed (where applicable in the form ofpharmaceutical preparations), and these are therefore preferred.

The free acid or free base forms of the compounds of the invention canbe prepared from the corresponding base addition salt or acid additionsalt from, respectively. For example a compound of the invention in anacid addition salt form can be converted to the corresponding free baseby treating with a suitable base (e.g., ammonium hydroxide solution,sodium hydroxide, and the like). A compound of the invention in a baseaddition salt form can be converted to the corresponding free acid bytreating with a suitable acid (e.g., hydrochloric acid, etc.).

Compounds of the invention in unoxidized form can be prepared fromN-oxides of compounds of the invention by treating with a reducing agent(e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride,sodium borohydride, phosphorus trichloride, tribromide, or the like) ina suitable inert organic solvent (e.g. acetonitrile, ethanol, aqueousdioxane, or the like) at 0 to 80° C.

Prodrug derivatives of the compounds of the invention can be prepared bymethods known to those of ordinary skill in the art (e.g., for furtherdetails see Saulnier M G, Langley D R, Kadow J F, Senter P D, Knipe J O,Tun M M, Vyas D M and Doyle T W (1994) Synthesis of etoposide phosphate,BMY-4048 1: a watersoluble clinically active prodrug of etoposide.Bioorg Med Chem Lett 4:2567-2572; and Rautio J, Kumpulainen H, HeimbachT, Oliyai R, Oh D, Järvinen T and Savolainen J (2008). For example, acompound of the invention can form a prodrug as shown:

Protected derivatives of the compounds of the invention can be made bymeans known to those of ordinary skill in the art. If one or more otherfunctional groups, for example carboxy, hydroxy, amino, sulfhydryl orthe like are or need to be protected in a starting material as describedherein or any other precursor, because they should not take part in thereaction or disturb the reaction, these are such groups as are usuallyused in the synthesis of peptide compounds, and also of cephalosporinsand penicillins, as well as nucleic acid derivatives and sugars.Protecting groups are such groups that are no longer present in thefinal compounds once they are removed, while groups that remain assubstituents are not protecting groups in the sense used here which aregroups that are added at a starting material or intermediate stage andremoved to obtain a final compound. Also in the case of conversions of acompound of the formula (I) into a different compound of the formula(I), protecting groups may be introduced and removed, if useful orrequired. The protecting groups may already be present in precursors andshould protect the functional groups concerned against unwantedsecondary reactions, such as acylations, etheri-fications,esterifications, oxidations, solvolysis, and similar reactions. It is acharacteristic of protecting groups that they lend themselves readily,i.e. without undesired secondary reactions, to removal, typically byacetolysis, protonolysis, solvolysis, reduction, photolysis or also byenzyme activity, for example under conditions analogous to physiologicalconditions, and that they are not present in the end-products. Thespecialist knows, or can easily establish, which protecting groups aresuitable with the reactions mentioned above and below.

The protection of such functional groups by such protecting groups, theprotecting groups themselves, and their removal reactions are describedfor example in standard reference works, such as J. F. W. McOmie,“Protective Groups in Organic Chemistry”, Plenum Press, London and NewYork 1973, in T. W. Greene, “Protective Groups in Organic Synthesis”,Third edition, Wiley, New York 1999, in “The Peptides”; Volume 3(editors: E. Gross and J. Meienhofer), Academic Press, London and NewYork 1981, in “Methoden der organischen Chemie” (Methods of organicchemistry), Houben Weyl, 4th edition, Volume 15/I, Georg Thieme Verlag,Stuttgart 1974, in H.-D. Jakubke and H. Jescheit, “Aminosäuren, Peptide,Proteine” (Amino acids, peptides, proteins), Verlag Chemie, Weinheim,Deerfield Beach, and Basel 1982, and in Jochen Lehmann, “Chemie derKohlenhydrate: Monosaccharide and Derivate” (Chemistry of carbohydrates:monosaccharides and derivatives), Georg Thieme Verlag, Stuttgart 1974.

Compounds of the present invention can be conveniently prepared, orformed during the process of the invention, as solvates (e.g.,hydrates). Hydrates of compounds of the present invention can beconveniently prepared by recrystallization from an aqueous/organicsolvent mixture, using organic solvents such as dioxin, tetrahydrofuranor methanol.

Compounds of the invention can be prepared as their individualstereoisomers by reacting a racemic mixture of the compound with anoptically active resolving agent to form a pair of diastereoisomericcompounds, separating the diastereomers and recovering the opticallypure enantiomers. While resolution of enantiomers can be carried outusing covalent diastereomeric derivatives of the compounds of theinvention, dissociable complexes are preferred (e.g., crystallinediastereomeric salts). Diastereomers have distinct physical properties(e.g., melting points, boiling points, solubilities, reactivity, etc.)and can be readily separated by taking advantage of thesedissimilarities. Diastereomeric mixtures for example may be separatedinto their individual diastereomers by means of fractionatedcrystallization, chromatography, solvent distribution, and similarprocedures. This separation may take place either at the level of astarting compound or in a compound of formula (I) itself. Enantiomersmay be separated through the formation of diastereomeric salts, forexample by salt formation with an enantiomer-pure chiral acid, or bymeans of chromatography, for example by HPLC, using chromatographicsubstrates with chiral ligands. The optically pure enantiomer is thenrecovered, along with the resolving agent, by any practical means thatwould not result in racemization. A more detailed description of thetechniques applicable to the resolution of stereoisomers of compoundsfrom their racemic mixture can be found in Jean Jacques, Andre Collet,Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John WileyAnd Sons, Inc., 1981.

In summary, the compounds of formula (I) can be made by a process, whichinvolves:

-   -   (a) those of reaction schemes I-IV; and    -   (b) optionally converting a compound of the invention into a        pharmaceutically acceptable salt;    -   (c) optionally converting a salt form of a compound of the        invention to a non-salt form;    -   (d) optionally converting an unoxidized form of a compound of        the invention into a pharmaceutically acceptable N-oxide;    -   (e) optionally converting an N-oxide form of a compound of the        invention to its unoxidized form;    -   (f) optionally resolving an individual isomer of a compound of        the invention from a mixture of isomers;    -   (g) optionally converting a non-derivatized compound of the        invention into a pharmaceutically acceptable prodrug derivative;        and    -   (h) optionally converting a prodrug derivative of a compound of        the invention to its non-derivatized form.

Insofar as the production of the starting materials is not particularlydescribed, the compounds are known or can be prepared analogously tomethods known in the art or as disclosed in the Examples hereinafter.

One of skill in the art will appreciate that the above transformationsare only representative of methods for preparation of the compounds ofthe present invention, and that other well known methods can similarlybe used.

EXAMPLES

The following examples illustrate the invention without limiting thescope thereof. In the examples provided, temperatures are given indegrees Celsius. Unless otherwise indicated, the reactions take place atroom temperature. Further, if not indicated otherwise, the analyticalHPLC conditions are as follows:

Condition 1: UPLC-MS, column Acquity BEH C18, 1.7 μm, 2.1×50 mm, oven at40° C., eluents: A=water+0.1% formic acid and B=MeCN+0.1% formic acid,gradient from 20% to 100% B in 4.3 min, flow 0.7 mL/min, detectionUV/VIS (DAD), ESI (+/−).

Condition 2: LC-MS, column Ascentis® Express C18 2.7 μm 2.1×30 mm, 50°C., eluents: A=water+0.05% formic acid+3.75 mM ammonium acetate andB=MeCN+0.04% formic acid, gradient from 5% to 95% B in 3.7 min, flow 1.2mL/min to 1.4 mL/min in 3.7 min, detection UV/VIS (DAD), ESI (+/−).

Condition 3: UPLC-MS, column Acquity HSS T3, 1.8 μm, 2.1×50 mm, oven at50° C., eluents: A=water+0.05% formic acid+3.75 mM ammonium acetate andB=MeCN+0.04% formic acid, gradient from 2% to 98% B in 1.40 min, then98% B for 0.75 min, flow 1.2 mL/min, detection UV/VIS (DAD), ESI (+/−).

Condition 4: HPLC, column Chromolith® Performance, RP-18e, 100×4.6mm+precolumn 5×4.6 mm at RT, eluents: A=water+0.1% formic acid andB=MeCN+0.1% formic acid, gradient from 2% to 100% B in 8 min, then 100%B for 2 min, flow 2.0 mL/min, detection UV/VIS (DAD).

Condition 5: LC-MS, column Ascentis® Express C18 2.7 μm 2.1×30 mm, 50°C., eluents: A=water+0.05% formic acid+3.75 mM ammonium acetate, andB=MeCN+0.04% formic acid, gradient from 10% to 95% B in 3.0 min, then95% B for 1.0 min, flow 1.2 mL/min, detection UV/VIS (DAD), ESI (+/−).

Condition 6: LC-MS, column Ascentis® Express C18 2.7 μm 2.1×30 mm, 50°C., eluents: A=water+0.05% TFA, and B=MeCN+0.04% TFA, gradient from 10%to 95% B in 3.0 min, then 95% B for 1.0 min, flow 1.2 mL/min, detectionUV/VIS (DAD), ESI (+).

Condition 7: UPLC-MS, direct injection, detection UV/VIS (DAD), ESI(+/−).

Condition 8: UPLC-MS, column Acquity BEH C18, 1.7 μm, 2.1×50 mm, oven at40° C., eluents: A=water+0.1% formic acid and B=MeCN+0.1% formic acid,gradient from 5% to 100% B in 2.0 min, flow 0.7 mL/min, detection UV/VIS(DAD), ESI (+/−).

Condition 9: UPLC-MS, column Acquity UPLC BEH C8 1.7 μm 2.1×50 mm, ovenat 45° C., eluents: A=water+0.1% TFA and B=MeCN, gradient from 2% to 95%B in 2.8 min, then 95% B for 0.5 min, flow 0.8 mL/min, detection UV/VIS(DAD), ESI (+).

Condition 10: HPLC, column CC125/4 Nucleosil® 100-3 C18HD, 4.0×125 mm,eluents: A=water+0.1% TFA and B=MeCN+0.1% TFA, gradient from 2% to 100%B in 7 min, then 100% B for 2 min and finally 100% to 2% B in 1 min,flow 1.0 mL/min, detection UV 215 nm.

Condition 11: similar condition as Condition 3, oven at 60° C. insteadof 50° C.

Further, if not indicated otherwise, the preparative HPLC conditions areas follows:

Condition 12: Preparative HPLC, Column: XBridge C18 30×100 mm, 5 μm;flow rate 30 mL/min; mobile phase: A=water+0.1% formic acid; B=MeCN;variable gradient, from initial % B to final % B, and runtime asspecified in the Examples.

Condition 13: Preparative HPLC, SunFire™ dc18 30×100 mm, 5 μm; flow rate30 mL/min; mobile phase: A=water+0.1% formic acid; B=MeCN; variablegradient, from initial % B to final % B, and runtime as specified in theExamples.

Condition 14: Preparative HPLC Gilson system, column SunFire™ prep C18OBD, 5 μm 30×100 mm, eluents: A=water+0.1% TFA and B=MeCN, gradient 5% Bfor 2 min, then 5% to 100% B in 20 min and finally 100% B in 3 min, flow30 mL/min, detection UV/VIS.

Preparative achiral SFC is done using the following system: Waters SFCTHAR100; flow rate 100 mL/min; mobile phase: A=supercritical CO₂;B=MeOH; variable gradient, from initial % B to final % B runtime andcolumns as specified in the Examples. Details for the columns:

Column 2-EP: column 2-Ethylpyridine (250×30 mm, 5 μm, 60 Å), Princeton

Column DEAP: column Diethyl amino (250×30 mm, 5 μm, 60 Å), Princeton

Column NH₂: column Amino Reprosil 70 NH2 (250×30 mm, 5 μm), Dr Maisch

Column Diol: column Diol (250×30 mm, 5 μm, 60 Å), Princeton

Column Silica: column silica (250×30 mm, 5 μm, 60 Å), Princeton

¹H-NMR spectra were recorded on a 300 MHz, or a 400 MHz, or a 600 MHzNMR spectrometer as indicated. Significant peaks are tabulated in theorder: multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m,multiplet; br. s, broad singlet) and number of protons.

In the following Examples, the abbreviations given below are used: aq.(aqueous); DAD (diode array detector); dba (dibenzylideneacetone); DCM(dichloromethane); DIPEA (diisopropyl-ethylamine); DMF(N,N-dimethylformamide); DME (dimethoxyethane); DMSO (dimethylsulfoxide); dppf (1,1′-bis(diphenylphosphino)ferrocene); eq.(equivalents); ESI (electrospray ionization); EtOAc (ethyl acetate);EtOH (ethanol); Et₂O (diethyl ether); h (hour); HPLC (high performanceliquid chromatography); HV (high vacuum); iPrOH (isopropanol); iPr₂O(diisopropyl ether); LC (liquid chromatography); M (molar); MeCN(acetonitrile); MeOH (methanol); min (minutes); mL (milliliters); MP(macroporous); MPLC (medium pressure liquid chromatography); MS (massspectrometry); MW (microwave); n-BuLi (n-butyllithium); NMP(N-methylpyrrolidinone); NMR (nuclear magnetic resonance); PL(polystyrene); PPh₃ (triphenylphosphine); RM (reaction mixture); RT(room temperature); sat. (saturated); sec (seconds); SFC (supercriticalfluid chromatography); Si-Thiol (3-mercaptopropyl modified silicagel)SPE (solid phase extraction); SPhos(2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl); TBME (methyltert-butyl ether); TFA (trifluoroacetic acid); TEA (triethylamine); THF(tetrahydrofuran); t_(R) (retention time); UPLC (ultra performanceliquid chromatography) and UV (Ultraviolet).

Example 1(S)-4-(3-Hydroxypyrrolidin-1-yl)-3-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)benzamide

(S)-3-Bromo-4-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)benzamide(Stage 1.1, 80 mg, 0.180 mmol), pyrimidin-5-ylboronic acid (66.8 mg,0.539 mmol), Pd(PPh₃)₂Cl₂ (7.57 mg, 10.78 μmol) and Na₂CO₃ (57.1 mg,0.539 mmol) were added to a MW vial and was treated with a mixture ofDME (762 μL), water (218 μL) and EtOH (109 μL). The vial was sealed,evacuated/purged with argon and the RM was subjected to MW irradiationat 80° C. for 2 h. The RM was cooled to RT, diluted with THF (1 mL) andtreated with Si-Thiol (Silicycle, 1.27 mmol/g, 70.7 mg, 0.090 mmol),filtered and the filtrate was evaporated off under reduced pressure togive a residue which), filtered and the filtrate was evaporated offunder reduced pressure to give a residue which was purified by flashchromatography (RediSep® Silica gel column, 4 g,cyclohexane/EtOAc-EtOH+0.1% NH₄OH (8:2), from 30% to 80% EtOAc-EtOH+0.1%NH₄OH (8:2) to yield the title compound as a yellow solid. UPLC-MS(condition 1) t_(R) 2.36 min, m/z=445.0 [M+H]⁺, m/z=443.1 [M−H]⁻; ¹H-NMR(400 MHz, DMSO-d₆) δ ppm 1.70-1.80 (m, 1H) 1.82-1.94 (m, 1H) 2.68 (dd,1H) 2.99-3.09 (m, 2H) 3.18-3.26 (m, 1H) 4.17-4.24 (m, 1H) 4.87 (d,J=3.67 Hz, 1H) 6.98 (d, J=8.80 Hz, 1H) 7.33 (d, J=8.31 Hz, 2H) 7.82-7.88(m, 3H) 7.94 (dd, J=8.80, 2.45 Hz, 1H) 8.86 (s, 2H) 9.16 (s, 1H) 10.09(s, 1H).

Stage 1.1(S)-3-Bromo-4-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-benzamide

A mixture of 3-bromo-4-fluoro-N-(4-(trifluoromethoxy)phenyl)benzamide(Stage 1.2, 100 mg, 0.264 mmol), (S)-pyrrolidin-3-ol (46.1 mg, 0.529mmol) and TEA (147 μL, 1.058 mmol) in DMSO (200 μL) was stirred at 90°C. for 16 h. The RM was diluted with 30 mL of TBME/EtOAc (1:1),sequentially washed 5 times with 0.5 M HCl and brine then evaporated todryness under reduced pressure. The crude product was purified by flashcolumn chromatography (RediSep® Silica gel column, 12 g,cyclohexane/EtOAc-EtOH+0.1% NH₄OH (9:1), from 10% to 50% EtOAc-EtOH+0.1%NH₄OH (9:1)) to afford the title compound as a white solid. UPLC-MS(condition 1) t_(R) 2.83 min, m/z=444.9 [M+H]⁺, m/z=443.0 [M−H]⁻; ¹H-NMR(400 MHz, DMSO-d₆) δ ppm 1.79-1.92 (m, 1H) 1.91-2.04 (m, 1H) 3.27 (d,J=10.76 Hz, 1H) 3.34-3.45 (m, 1H) 3.67 (dd, 1H) 3.81 (dd, J=10.39, 4.77Hz, 1H) 4.30-4.42 (m, 1H) 4.97 (d, J=3.42 Hz, 1H) 6.93 (d, J=8.80 Hz,1H) 7.34 (d, J=8.56 Hz, 2H) 7.81-7.90 (m, 3H) 8.13 (d, J=2.20 Hz, 1H)10.18 (s, 1H).

Stage 1.2 3-Bromo-4-fluoro-N-(4-(trifluoromethoxy)phenyl)-benzamide

SOCl₂ (2.92 mL, 40.0 mmol) and DMF (0.5 mL) were added dropwise to asuspension of 3-bromo-4-fluorobenzoic acid (1.752 g, 8 mmol) in toluene(20 mL) and the RM was stirred at 80° C. for 1 h. The solvent wasevaporated off under reduced pressure and the residue was diluted withTHF (15 mL). DIPEA (2.79 mL, 16.00 mmol) was added and the mixture wascooled to 0° C., treated with a solution of 4-trifluoromethoxyaniline(1.181 mL, 8.80 mmol) in THF (5 mL) and stirred for 1 h. The RM wastreated with aq. 1 M HCl (50 mL), and extracted with TBME. The combinedextracts were washed with aq. 1 M HCl, aq. 1 M NaOH and brine, driedover MgSO₄ and the solvent was evaporated off under reduced pressure togive a residue was crystallized from n-heptane/DCM to afford the titlecompound as a white solid. UPLC-MS (Condition 1) t_(R)=3.18 min,m/z=377.9/379.9 [M+H]⁺, m/z=375.9/377.9 [M−H]⁻; ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 7.38 (d, J=8.6 Hz, 2H) 7.56 (t, J=8.7 Hz, 1H) 7.87 (d,J=9.0 Hz, 2H) 8.00-8.06 (m, 1H) 8.32 (dd, J=6.6, 2.2 Hz, 1H) 10.50 (s,1H).

Example 2(R)-4-(3-Hydroxypyrrolidin-1-yl)-3-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)benzamide

(R)-3-Bromo-4-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)benzamide(Stage 2.1, 80 mg, 0.180 mmol), pyrimidin-5-ylboronic acid (66.8 mg,0.539 mmol), Pd(PPh₃)₂Cl₂ (7.57 mg, 10.78 μmol) and Na₂CO₃ (57.1 mg,0.539 mmol) were added to a MW vial and treated with a mixture of DME(762 μL), water (218 μL) and EtOH (109 μL). The vial sealed,evacuated/purged with argon and then the RM was subjected to MWirradiation at 80° C. for 2 h. The RM was cooled to RT, diluted with THF(1 mL), treated with Si-Thiol (Silicycle, 1.27 mmol/g, 70.7 mg, 0.090mmol), filtered and the filtrate was evaporated off under reducedpressure to give a residue which was purified by flash chromatography(RediSep® Silica gel column, 4 g, cyclohexane/EtOAc-EtOH+0.1% NH4OH(8:2), from 30% to 80% EtOAc-EtOH+0.1% NH4OH (8:2)) to yield the titlecompound as an off-white solid. UPLC-MS (condition 1) t_(R)=2.37 min,m/z=445.0 [M+H]⁺, m/z=443.2 [M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm1.70-1.81 (m, 1H) 1.82-1.93 (m, 1H) 2.68 (dd, J=10.15, 1.10 Hz, 1H)2.97-3.11 (m, 2H) 3.17-3.27 (m, 1H) 4.17-4.25 (m, 1H) 4.87 (d, J=3.67Hz, 1H) 6.98 (d, J=9.05 Hz, 1H) 7.33 (d, J=8.31 Hz, 2H) 7.79-7.90 (m,3H) 7.94 (dd, J=8.80, 2.20 Hz, 1H) 8.86 (s, 2H) 9.16 (s, 1H) 10.09 (s,1H).

Stage 2.1(R)-3-Bromo-4-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-benzamide

A mixture of 3-bromo-4-fluoro-N-(4-(trifluoromethoxy)phenyl)benzamide(Stage 1.2, 100 mg, 0.264 mmol), (R)-pyrrolidin-3-ol (46.1 mg, 0.529mmol) and TEA (147 μL, 1.058 mmol) in DMSO (199 μL) was stirred at 90°C. for 16 h. The RM was diluted with TBME/EtOAc (1:1) (30 mL), washedwith 0.5 M HCl (3×5 mL) and brine (5 mL) and the solvent was evaporatedoff under reduced pressure to give a crude product that was purified byflash chromatography (RediSep® Silica gel column, 4 g,cyclohexane/EtOAc-EtOH+0.1% NH4OH (8:2), from 30% to 80% EtOAc-EtOH+0.1%NH4OH (8:2)) to yield the title compound as an off-white solid. UPLC-MS(condition 1) t_(R)=2.83 min, m/z=444.9/446.9 [M+H]⁺, m/z=443.0/445.0[M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.80-1.92 (m, 1H) 1.92-2.04 (m,1H) 3.24-3.30 (m, 1H). 3.36-3.46 (m, 1H) 3.60-3.72 (m, 1H) 3.81 (dd,J=10.51, 4.65 Hz, 1H) 4.36 (d, J=2.69 Hz, 1H) 4.97 (d, J=3.42 Hz, 1H)6.93 (d, J=8.80 Hz, 1H) 7.34 (d, J=8.56 Hz, 2H) 7.80-7.90 (m, 3H) 8.14(d, J=1.96 Hz, 1H) 10.19 (s, 1H).

Example 3(R)-4-(3-Hydroxypyrrolidin-1-yl)-3-(2-methylpyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)benzamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 1 using(R)-3-bromo-4-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)benzamide(Stage 2.1) and2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine toafford a white solid. UPLC-MS (condition 1) t_(R)=2.46 min,m/z=459.1-460.1 [M+H]⁺, m/z=457.2-458.2 [M−H]⁻; ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 1.76 (d, J=3.91 Hz, 1H) 1.82-1.93 (m, 1H) 2.65-2.72 (m,1H) 2.68 (s, 3H) 3.00-3.11 (m, 2H) 3.18-3.27 (m, 1H) 4.17-4.25 (m, 1H)4.86 (d, J=3.67 Hz, 1H) 6.96 (d, J=8.80 Hz, 1H) 7.33 (d, J=8.56 Hz, 2H)7.81 (d, J=2.20 Hz, 1H) 7.83-7.88 (m, 2H) 7.92 (dd, J=8.80, 2.20 Hz, 1H)8.73 (s, 2H) 10.08 (s, 1H).

Example 4(R)-4-(3-Hydroxypyrrolidin-1-yl)-3-(2-methoxypyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)benzamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 1 using(R)-3-bromo-4-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)benzamide(Stage 2.1) and (6-methoxypyridin-3-yl)boronic acid to afford a whitesolid. LC-MS (Condition 2) t_(R)=1.96 min, m/z=475.2-476.2 [M+H]⁺,m/z=573.1 [M+TFA-H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.70-1.80 (m, 1H)1.82-1.94 (m, 1H) 2.72 (d, J=9.29 Hz, 1H) 3.01-3.13 (m, 2H) 3.19-3.28(m, 1H) 3.98 (s, 3H) 4.18-4.25 (m, 1H) 4.87 (d, J=3.42 Hz, 1H) 6.95 (d,J=8.80 Hz, 1H) 7.34 (d, J=8.80 Hz, 2H) 7.79 (d, J=1.96 Hz, 1H) 7.87 (d,2H) 7.91 (dd, J=8.80, 2.20 Hz, 1H) 8.64 (s, 2H) 10.07 (s, 1H).

Example 5(R)-4-(3-Hydroxypyrrolidin-1-yl)-3-(pyridin-3-yl)-N-(4-(trifluoromethoxy)phenyl)benzamide

The title compound was prepared in analogous fashion to that describedin Example 1 using(R)-3-bromo-4-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)benzamide(Stage 2.1) and pyridin-3-ylboronic acid to afford a white solid.UPLC-MS (condition 1) t_(R)=1.94 min, m/z=444.1 [M+H]⁺, m/z=442.1[M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.68-1.79 (m, 1H) 1.85 (dt,J=8.62, 4.37 Hz, 1H) 2.66 (d, J=9.78 Hz, 1H) 2.98-3.07 (m, 2H) 3.16-3.25(m, 1H) 4.18 (br. s, 1H) 4.84 (br. s, 1H) 6.95 (d, J=8.80 Hz, 1H) 7.33(d, J=8.56 Hz, 2H) 7.50 (dd, J=7.82, 4.89 Hz, 1H) 7.80 (d, J=2.20 Hz,1H) 7.81-7.89 (m, 3H) 7.92 (dd, J=8.68, 2.32 Hz, 1H) 8.56 (d, J=3.91 Hz,1H) 8.65 (br. s, 1H) 10.10 (s, 1H).

Example 6(R)-4-(3-Hydroxypyrrolidin-1-yl)-3-(6-methylpyridin-3-yl)-N-(4-(trifluoromethoxy)phenyl)benzamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 1 using(R)-3-bromo-4-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)benzamide(Stage 2.1) and (6-methylpyridin-3-yl)boronic acid to afford a whitesolid. UPLC-MS (condition 1) t_(R)=1.92, m/z=458.1-459.1 [M+H]⁺,m/z=456.2-457.3 [M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.69-1.78 (m,1H) 1.81-1.91 (m, 1H) 2.53 (s, 3H) 2.67 (d, J=10.27 Hz, 1H) 3.00-3.08(m, 2H) 3.18-3.28 (m, 1H) 4.16-4.21 (m, 1H) 4.83 (d, J=3.42 Hz, 1H) 6.93(d, J=9.05 Hz, 1H) 7.30-7.36 (m, 3H) 7.68 (dd, J=7.95, 2.32 Hz, 1H) 7.77(d, J=2.20 Hz, 1H) 7.84-7.92 (m, 3H) 8.48 (d, J=1.96 Hz, 1H) 10.09 (s,1H).

Example 74-((3S,4S)-3,4-Dihydroxypyrrolidin-1-yl)-3-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)benzamide

3-Bromo-4-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)benzamide(Stage 7.1, 60 mg, 0.13 mmol), pyrimidin-5-ylboronic acid (66.6 mg,0.325 mmol), Pd(PPh₃)₂Cl₂ (9.13 mg, 0.013 mmol) and Na₂CO₃ (68.9 mg,0.650 mmol) were added to a MW vial. The vial was sealed,evacuated/purged with argon, and DME (552 μL), water (158 μL), EtOH (79μL) were added. The RM was then subjected to MW irradiation at 120° C.for 10 min. The RM was diluted with DME (2 mL), treated with Si-Thiol(Silicycle, 1.27 mmol/g, 102 mg, 0.130 mmol), filtered and the filtratewas evaporated off under reduced pressure to give a residue which waspurified by preparative HPLC (Condition 12, from 20% to 50% in 18 min)to yield the title compound as a white solid. UPLC-MS (condition 1)t_(R)=2.10 min, m/z=461.0 [M+H]⁺, m/z=459.0 [M−H]⁻; ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 2.75 (d, J=10.27 Hz, 2H) 3.27 (dd, J=10.39, 3.55 Hz, 2H)3.88 (br. s, 2H) 5.07 (d, J=3.42 Hz, 2H) 6.97 (d, J=8.80 Hz, 1H) 7.34(d, J=8.31 Hz, 2H) 7.82-7.90 (m, 3H) 7.94 (dd, J=8.80, 2.45 Hz, 1H) 8.85(s, 2H) 9.17 (s, 1H) 10.10 (s, 1H).

Stage 7.13-Bromo-4-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-benzamide

A solution of 3-bromo-4-fluoro-N-(4-(trifluoromethoxy)phenyl)benzamide(Stage 1.2, 500 mg, 1.322 mmol), (3S,4S)-pyrrolidine-3,4-diol (205 mg,1.984 mmol) and TEA (553 μL, 3.97 mmol) in DMSO (994 μL) was stirred at90° C. for 24 h. Additional (3S,4S)-pyrrolidine-3,4-diol, (68.2 mg,0.661 mmol) and TEA (183 μL, 1.322 mmol) were added and mixture wasstirred at 100° C. for 16 h. The cooled treated with 0.5 M HCl (20 mL)and extracted with TBME/EtOAc (1:1). The combined extracts were washedwith 0.5 M HCl (20 mL) and brine, dried over MgSO₄ and the solvent wasevaporated off under reduced pressure to give a residue which wascrystallised from cyclohexane/EtOAc to afford the title compound as anoff-white solid. UPLC-MS (condition 1) t_(R)=2.41 min, m/z=460.9/462.9[M+H]⁺, m/z=459.0/461.0 [M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 3.24 (d,J=10.76 Hz, 2H) 3.88 (dd, J=10.51, 3.67 Hz, 2H) 4.02 (br. s, 2H) 5.15(d, J=3.18 Hz, 2H) 6.89 (d, J=8.80 Hz, 1H) 7.34 (d, J=8.31 Hz, 2H) 7.84(dd, J=8.68, 2.08 Hz, 1H) 7.85-7.89 (m, 2H) 8.13 (d, J=2.20 Hz, 1H)10.17 (s, 1H).

Example 84-((3S,4S)-3,4-Dihydroxypyrrolidin-1-yl)-3-(pyridin-3-yl)-N-(4-(trifluoromethoxy)phenyl)benzamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 7 using3-bromo-4-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)benzamide(Stage 7.1) and pyridin-3-ylboronic acid to afford a yellow solid.UPLC-MS (condition 1) t_(R)=1.67 min, m/z=460.0 [M+H]⁺, m/z=458.0[M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 2.73 (d, J=10.76 Hz, 2H) 3.24(dd, J=10.51, 3.67 Hz, 2H) 3.85 (d, J=2.20 Hz, 2H) 5.03 (br. s, 2H) 6.92(d, J=8.80 Hz, 1H) 7.33 (d, J=8.31 Hz, 2H) 7.48 (dd, J=7.46, 5.26 Hz,1H) 7.76-7.83 (m, 2H) 7.83-7.89 (m, 2H) 7.91 (dd, J=8.80, 2.20 Hz, 1H)8.55 (dd, J=4.77, 1.59 Hz, 1H) 8.62 (d, J=1.47 Hz, 1H) 10.10 (s, 1H).

Example 94-((3S,4S)-3,4-Dihydroxypyrrolidin-1-yl)-3-(6-methylpyridin-3-yl)-N-(4-(trifluoromethoxy)phenyl)benzamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 7 using3-bromo-4-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)benzamide(Stage 7.1) and (6-methylpyridin-3-yl)boronic acid to afford a yellowsolid. UPLC-MS (condition 1) t_(R)=1.65 min, m/z=474.0 [M+H]⁺, m/z=472.1[M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 2.53 (s, 3H) 2.74 (d, J=10.76Hz, 2H) 3.25 (dd, J=10.51, 3.67 Hz, 2H) 3.85 (br. s, 2H) 5.03 (br. s,2H) 6.90 (d, J=8.80 Hz, 1H) 7.27-7.38 (m, 3H) 7.68 (dd, J=7.82, 2.20 Hz,1H) 7.77 (d, J=2.20 Hz, 1H) 7.85-7.88 (m, 2H) 7.87-7.91 (m, 1H) 8.48 (d,J=2.20 Hz, 1H) 10.09 (s, 1H).

Example 104-(cis-3,4-Dihydroxypyrrolidin-1-yl)-3-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)benzamide

3-Bromo-4-((3S,4R)-3,4-dihydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)benzamide(Stage 10.1, 60 mg, 0.13 mmol), pyrimidin-5-ylboronic acid (32.2 mg,0.260 mmol), Pd(PPh₃)₂Cl₂ (9.11 mg, 0.013 mmol) and Na₂CO₃ (55.0 mg,0.519 mmol) were added to a MW vial and treated with a mixture of DME(551 μL), water (157 μL) and EtOH (79 μL). Vial was sealed,evacuated/purged with argon and subjected to MW irradiation at 125° C.for 10 min. The RM was diluted with DME (3 mL), treated with Si-Thiol(Silicycle, 1.44 mmol/g, 54.1 mg, 0.078 mmol), centrifuged, thesupernatant was filtered and the solvent was evaporated off underreduced pressure to give a residue which was purified by preparative SFC(Column DEAP, isocratic 25% in 9 min.) to yield the title compound as awhite solid. UPLC-MS (Condition 3) t_(R)=0.83 min, m/z=462.1 [M+H]⁺,m/z=460.1 [M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 3.05 (dd, J=10.76,4.16 Hz, 2H) 3.26 (dd, J=10.51, 4.89 Hz, 2H) 3.98 (t, J=3.91 Hz, 2H)4.89 (br. s, 2H) 7.35 (d, J=8.56 Hz, 2H) 7.79-7.90 (m, 2H) 8.10 (d,J=2.20 Hz, 1H) 8.79 (d, J=2.20 Hz, 1H) 8.88 (s, 2H) 9.20 (s, 1H) 10.17(s, 1H).

Stage 10.13-Bromo-4-((3S,4R)-3,4-dihydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-benzamide

A solution of 3-bromo-4-fluoro-N-(4-(trifluoromethoxy)phenyl)benzamide(Stage 1.2, 500 mg, 1.32 mmol), (3S,4R)-pyrrolidine-3,4-diol (170 mg,1.65 mmol) and TEA (369 μL, 2.64 mmol) in DMSO (1322 μL) was stirred at90° C. for 20 h. The RM was treated with 0.5 M HCl (15 mL) and extractedwith EtOAc (30 mL). The aq. phase was back-extracted with EtOAc (2×20mL) and the combined organic layers were washed with sat. NaHCO₃ andbrine, and dried over Na₂SO₄. The crude product was purified by flashchromatography (RediSep® Silica gel column, 40 g, cyclohexane/EtOAc,from 50% to 100% EtOAc) to yield the title compound as a white amorphoussolid. UPLC-MS (Condition 3) t_(R)=1.02 min, m/z=461.2-463.1 [M+H]⁺,m/z=459.1-461.1 [M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 3.40 (dd,J=9.90, 4.52 Hz, 2H) 3.67 (dd, J=9.66, 5.26 Hz, 2H) 4.06-4.16 (m, 2H)4.94 (d, J=4.65 Hz, 2H) 6.86 (d, J=8.80 Hz, 1H) 7.34 (d, J=8.31 Hz, 2H)7.80-7.91 (m, 3H) 8.13 (d, J=2.20 Hz, 1H) 10.17 (s, 1H).

Example 114-(3-Hydroxy-3-methylpyrrolidin-1-yl)-3-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)benzamide

3-Bromo-4-(3-hydroxy-3-methylpyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)benzamide(Stage 11.1, 83 mg, 0.18 mmol), pyrimidin-5-ylboronic acid (66.9 mg,0.540 mmol) and Na₂CO₃ (57.2 mg, 0.540 mmol) were added to a MW vial andtreated with a mixture of DME (764 μL), water (218 μL) and EtOH (109μL). The vial was sealed, evacuated/purged with argon and the RM wassubjected to MW irradiation at 80° C. for 2 h. The RM was cooled to RT,diluted with THF (1 mL) and treated with Si-Thiol (Silicycle, 1.27mmol/g, 70.9 mg, 0.090 mmol), filtered and the filtrate was evaporatedoff under reduced pressure to give a residue which was purified by flashchromatography (RediSep® Silica gel column, 4 g,cyclohexane/EtOAc-EtOH+0.1% NH4OH (8:2), from 20% to 70% EtOAc-EtOH+0.1%NH4OH (8:2)) to yield the title compound as a yellow solid. UPLC-MS(condition 1) t_(R)=2.47 min, m/z=459.0 [M+H]⁺, m/z=457.1 [M−H]⁻; ¹H-NMR(400 MHz, DMSO-d₆) δ ppm 1.19 (s, 3H) 1.68-1.83 (m, 2H) 2.77 (d, J=9.78Hz, 1H) 2.87 (d, 1H) 2.97-3.07 (m, 1H) 3.21-3.30 (m, 1H) 4.72 (s, 1H)6.96 (d, J=9.05 Hz, 1H) 7.33 (d, J=8.56 Hz, 2H) 7.80-7.89 (m, 3H) 7.94(dd, J=8.93, 2.32 Hz, 1H) 8.86 (s, 2H) 9.16 (s, 1H) 10.09 (s, 1H), 9.29ppm.

Stage 11.13-Bromo-4-(3-hydroxy-3-methylpyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-benzamide

A mixture of 3-bromo-4-fluoro-N-(4-(trifluoromethoxy)phenyl)benzamide(Stage 1.2, 100 mg, 0.264 mmol), 3-methylpyrrolidine-3-ol hydrochloride(72.8 mg, 0.529 mmol), and TEA (147 μL, 1.058 mmol) in DMSO (199 μL) wasstirred at 90° C. for 16 h. Additional TEA (73.7 μL, 0.529 mmol) wasadded to the mixture and stirring was continued for 72 h at 100° C. Thecooled RM was diluted with TBME/EtOAc (1:1)(30 mL), sequentially washed0.5 M HCl (3×5 mL), brine (5 mL) and then evaporated to dryness underreduced pressure. The crude product was purified by flash chromatography(RediSep® Silica gel column, 12 g, cyclohexane/EtOAc-EtOH+0.1% NH4OH(9:1), from 20% to 60% EtOAc-EtOH+0.1% NH4OH (9:1)) to yield the titlecompound as a white solid. UPLC-MS (condition 1) t_(R)=2.98 min,m/z=459/461.0 [M+H]+, m/z=457/459 [M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δppm 1.35 (s, 3H) 1.77-1.95 (m, 2H) 3.32-3.35 (m, 1H) 3.37-3.48 (m, 1H)3.65 (d, J=10.03 Hz, 1H) 3.75 (td, J=9.41, 7.09 Hz, 1H) 4.79 (s, 1H)6.90 (d, J=8.80 Hz, 1H) 7.34 (d, J=8.31 Hz, 2H) 7.81-7.91 (m, 3H) 8.13(d, J=1.96 Hz, 1H) 10.17 (s, 1H).

Example 126-(3-Hydroxypyrrolidin-1-yl)-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

5-Bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.2,60 mg, 0.152 mmol), (Rac.)-pyrrolidin-3-ol (15.86 mg, 0.182 mmol), andDIPEA (53.0 μL, 0.303 mmol) in iPrOH (250 μL) were added to a MW vialand subjected to MW irradiation at 110° C. for 20 min. The RM was thentransferred into a MV vial containing pyrimidin-5-ylboronic acid (56.4mg, 0.455 mmol), Pd(PPh₃)₂Cl₂ (10.65 mg, 0.015 mmol), Na₂CO₃ (80 mg,0.758 mmol) and treated with a mixture of DME (600 μL)—water (200 μL).The vial was sealed, evacuated/purged with argon and the RM wassubjected to MW irradiation at 80° C. for 2 h. The RM was cooled to RT,diluted with THF (1.5 mL), treated with Si-Thiol (Silicycle, 59.7 mg,0.076 mmol), filtered and the filtrate was evaporated off under reducedpressure to give a residue which was purified by preparative HPLC(Condition 13, 30% for 0.2 min then 30% to 60% in 12 min) to yield thetitle compound as a white solid. UPLC-MS (condition 1) t_(R)=2.01 min,m/z=446.0 [M+H]⁺, m/z=444.1 [M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm1.70-1.79 (m, 1H) 1.79-1.90 (m, 1H) 2.88 (d, J=11.0 Hz, 1H) 3.18-3.27(m, 2H) 3.38-3.43 (m, 1H) 4.17-4.25 (m, 1H) 4.79-5.01 (m, 1H) 7.35 (d,J=8.3 Hz, 2H) 7.85 (d, J=4.9 Hz, 2H) 8.10 (d, J=2.4 Hz, 1H) 8.79 (d,J=2.4 Hz, 1H) 8.89 (s, 2H) 9.19 (s, 1H) 10.18 (s, 1H).

Stage 12.15-Bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

5-Bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.2,1 g, 2.53 mmol) and (Rac.)-pyrrolidin-3-ol (264 mg, 3.03 mmol) and DIPEA(883 μL, 5.06 mmol), in iPrOH (4213 μL) were added a MW vial and heatedat 140° C. for 30 min. The RM was evaporated to dryness under reducedpressure, treated with 0.5 M HCl (10 mL) and EtOAc (20 mL) and extractedwith EtOAc. The combined extracts were washed with water, dried overMgSO₄ and evaporated to dryness under reduced pressure. Trituration ofthe residue in cyclohexane and filtration of the solid afforded thetitle compound as an off-white solid. UPLC-MS (condition 1) t_(R)=2.63min, m/z=445.9-447.9 [M+H]⁺, m/z=444.0-446.0 [M−H]⁻; ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 1.80-2.02 (m, 2H) 3.58 (d, J=11.49 Hz, 1H) 3.67-3.79 (m,1H) 3.82-3.93 (m, 2H) 4.32-4.40 (m, 1H) 4.98 (br. s, 1H) 7.36 (d, J=8.56Hz, 2H) 7.86 (d, J=9.05 Hz, 2H) 8.35 (d, J=1.96 Hz, 1H) 8.69 (d, J=1.96Hz, 1H) 10.23 (s, 1H).

Stage 12.2 5-Bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide

SOCl₂ (1.089 mL, 14.92 mmol) and DMF (0.01 mL) were added dropwise to asuspension of 5-bromo-6-chloronicotinic acid (1.176 g, 4.97 mmol) intoluene (10 mL) and the RM was stirred at 85° C. for 2 h. The solventwas evaporated off under reduced pressure and the residue was dilutedwith THF (10 mL). DIPEA (1.74 mL, 9.95 mmol) was added and the mixturewas cooled to −15° C. under argon atmosphere, treated with a solution of4-trifluoromethoxyaniline (0.701 mL, 5.22 mmol) in THF (10 mL) andstirred at RT for 1 h. The solvent was off under reduced pressure andthe residue was treated with aq. 1M HCl (50 mL), and extracted withTBME/EtOAc (4:1). The combined extracts were washed with aq. 1 M HCl,sat. aq. Na₂CO₃ and brine, dried over MgSO₄ and the solvent wasevaporated off under reduced pressure to give the crude product waspurified by flash chromatography (Biotage Silica gel column, 50 g,cyclohexane/EtOAc from 5% to 25% EtOAc) to afford the title compound asan off-white solid. UPLC-MS (Condition 1) t_(R)=3.09 min,m/z=394.9/396.8 [M+H]⁺, m/z=393.0/394.9 [M−H]⁻; ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 7.40 (d, J=8.6 Hz, 2H) 7.86 (d, J=9.0 Hz, 2H) 8.73 (d,J=2.2 Hz, 1H) 8.92 (d, J=2.0 Hz, 1H) 10.69 (s, 1H).

Example 13-27

The following examples were prepared in an analogous fashion to thatdescribed in Example 12 using5-bromo-6-(3-hydroxy-3-methylpyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 12.2) and starting material as indicated.

Starting material Ex. Structure/Name Analytics 13

3-methylpyrrolidin-3-ol hydrochloride UPLC-MS (condition 1) t_(R) = 2.59min, m/z = 460.0 [M + H]⁺, m/z = 458.0 [M − H]⁻; ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 1.20 (s, 3 H) 1.65- 1.85 (m, 2 H) 2.96 (d, 1 H) 3.03 (d,1 H) 3.17- 3.25 (m, 1 H) 3.44-3.47 (m, 1 H) 4.72 (br. s, 0 H) 7.35 (d, J= 8.31 Hz, 2 H) 7.85 (d, J = 4.65 Hz, 2 H) 8.09 (d, J = 2.20 Hz, 1 H)8.78 (d, J = 2.20 Hz, 1 H) 8.89 (s, 2 H) 9.19 (s, 1 H) 10.16 (s, 1 H).14

pyrrolidin-3-ylmethanol UPLC-MS (Condition 9) t_(R) = 1.57 min, m/z =460.4 [M + H]⁺. 15

N-(pyrrolidin-3-yl)acetamide UPLC-MS (Condition 9) t_(R) = 1.63 min, m/z= 487.4 [M + H]⁺. 16

2-methyloctahydropyrrolo[3,4-c]pyrrole UPLC-MS (Condition 3) t_(R) =0.76 min, m/z = 485.2 [M + H]⁺, 483.1 [M − H]⁻. 17

2,7-diazaspiro[4.4]nonan-1-one UPLC-MS (Condition 9) t_(R) = 1.66 min,m/z = 499.4 [M + H]⁺. 18

12/12 and 2,3-dihydro-1H-pyrrolo[3,4- c]pyridine UPLC-MS (Condition 9)t_(R) = 1.60 min, m/z = 479.4 [M + H]⁺. 19

piperidin-3-ylmethanol UPLC-MS (Condition 9) t_(R) = 1.82 min, m/z =474.4 [M + H]⁺. 20

N-(piperidin-3-yl)acetamide UPLC-MS (Condition 9) t_(R) = 1.82 min, m/z= 501.5 [M + H]⁺. 21

piperidine-4-carboxamide UPLC-MS (Condition 9) t_(R) = 1.73 min, m/z =487.5 [M + H]⁺. 22

piperidin-4-ol UPLC-MS (Condition 9) t_(R) = 1.75 min, m/z = 460.4 [M +H]⁺. 23

(R)-piperidine-3-carbonitrile UPLC-MS (Condition 9) t_(R) = 2.00 min,m/z = 469.4 [M + H]⁺. 24

(S)-piperidine-3-carbonitrile UPLC-MS (Condition 9) t_(R) = 2.00 min,m/z = 469.4 [M + H]⁺. 25

3-hydroazetidine hydrochloride UPLC-MS (condition 1) t_(R) = 1.99 min,m/z = 432.0 [M + H]⁺, m/z = 430.1 [M − H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δppm 3.44-3.55 (m, 2 H) 3.85-3.98 (m, 2 H) 4.31-4.46 (m, 1 H) 5.59 (d, J= 6.1 Hz, 1 H) 7.36 (d, J = 8.6 Hz, 2 H) 7.85 (d, J = 9.3 Hz, 2 H) 8.10(d, J = 2.2 Hz, 1 H) 8.80 (d, J = 2.2 Hz, 1 H) 8.91 (s, 2 H) 9.22 (s, 1H) 10.22 (s, 1 H). 26

1-methylpiperazine UPLC-MS (Condition 9) t_(R) = 1.56 min, m/z = 459.4[M + H]⁺. 27

N-methyltetrahydro-2H-pyran-4-amine UPLC-MS (Condition 9) t_(R) = 1.94min, m/z = 474.4 [M + H]⁺.

Example 286-(3-Hydroxypyrrolidin-1-yl)-5-(2-methoxypyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(60 mg, 0.134 mmol), (6-methoxypyridin-3-yl)boronic acid (62.1 mg, 0.403mmol), Pd(PPh₃)₂Cl₂ (5.66 mg, 8.07 μmol) and Na₂CO₃ (42.8 mg, 0.403mmol) were added to a MW vial and treated with a mixture of DME (570μL), water (163 μL) and EtOH (81 μL). The vial was sealed,evacuated/purged with argon and the RM was subjected to MW irradiationat 80° C. for 2 h. The RM was cooled to RT, diluted with THF (2 mL),treated with Si-Thiol (Silicycle, 1.27 mmol/g, 52.9 mg, 0.067 mmol),filtered and the filtrate was evaporated off under reduced pressure togive a residue which was purified by preparative HPLC (Condition 13,from 25% to 55% in 12 min) to afford the title compound as an off-whitesolid. UPLC-MS (condition 1) t_(R)=2.19 min, m/z=473.0 [M+H]⁺, m/z=474.1[M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.68-1.80 (m, 1H) 1.79-1.92 (m,1H) 2.94 (d, J=11.00 Hz, 1H) 3.21-3.29 (m, 2H) 3.35-3.46 (m, 1H) 3.98(s, 3H) 4.18-4.29 (m, 1H) 4.87 (br. s, 1H) 7.35 (d, J=8.80 Hz, 2H) 7.85(d, J=9.05 Hz, 2H) 8.02 (d, J=2.45 Hz, 1H) 8.67 (s, 2H) 8.77 (d, J=2.20Hz, 1H) 10.15 (s, 1H).

Example 292-(3-Hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 28 using5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 12.1) and pyridin-3-ylboronic acid to afford a white solid.UPLC-MS (condition 1) t_(R)=1.78 min, m/z=445.0 [M+H]⁺, m/z=443.1[M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.67-1.78 (m, 1H) 1.78-1.90 (m,1H) 2.88 (d, J=11.25 Hz, 1H) 3.13-3.28 (m, 2H) 3.35-3.45 (m, 1H) 4.20(br. s, 1H) 4.85 (d, J=3.42 Hz, 1H) 7.35 (d, J=8.80 Hz, 2H) 7.50 (dd,J=7.82, 4.89 Hz, 1H) 7.82 (d, J=8.07 Hz, 1H) 7.86 (d, J=9.05 Hz, 2H)8.04 (d, J=2.20 Hz, 1H) 8.59 (dd, J=4.77, 1.34 Hz, 1H) 8.65 (d, J=1.96Hz, 1H) 8.78 (d, J=2.20 Hz, 1H) 10.17 (s, 1H).

Example 302-(3-Hydroxypyrrolidin-1-yl)-6′-methyl-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 28 using5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 12.1) and (6-methylpyridin-3-yl)boronic acid to afford anoff-white solid. UPLC-MS (condition 1) t_(R)=1.61 min, m/z=459.0 [M+H]⁺,m/z=457.2 [M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.67-1.77 (m, 1H)1.77-1.88 (m, 1H) 2.53 (s, 3H) 2.88 (d, J=11.49 Hz, 1H) 3.15-3.27 (m,2H) 3.38 (td, J=9.96, 7.21 Hz, 1H) 4.15-4.22 (m, 1H) 4.84 (d, J=3.42 Hz,1H) 7.34 (d, J=8.07 Hz, 3H) 7.68 (dd, J=7.95, 2.32 Hz, 1H) 7.85 (d,J=9.05 Hz, 2H) 7.99 (d, J=2.45 Hz, 1H) 8.48 (d, J=2.20 Hz, 1H) 8.75 (d,J=2.45 Hz, 1H) 10.15 (s, 1H).

Example 312-(3-Hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-[3,4′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 28 using5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 12.1) and 4-pyridineboronic acid to afford a yellow solid.UPLC-MS (condition 1) t_(R)=1.62 min, m/z=445.0 [M+H]⁺, m/z=443.1[M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.70-1.80 (m, 1H) 1.85 (dd,J=8.68, 4.28 Hz, 1H) 2.85 (d, J=11.49 Hz, 1H) 3.24 (dd, J=11.25, 4.16Hz, 2H) 3.40-3.53 (m, 1H) 4.21 (br. s, 1H) 4.87 (br. s, 1H) 7.35 (d,J=8.80 Hz, 2H) 7.45 (d, J=5.87 Hz, 2H) 7.86 (d, J=9.29 Hz, 2H) 8.07 (d,J=2.45 Hz, 1H) 8.65 (d, J=5.14 Hz, 2H) 8.78 (d, J=2.20 Hz, 1H) 10.21 (s,1H).

Example 322-(3-Hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-6′-(trifluoromethyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 28 using5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 12.1) and (6-(trifluoromethyl)pyridin-3-yl)boronic acid to affordan off-white solid. UPLC-MS (condition 1) t_(R)=2.77 min, m/z=513.0[M+H]⁺, m/z=511.1 [M−H]⁻; ¹H-NMR (400 MHz, DMSO-d6) δ ppm 1.70-1.80 (m,1H) 1.80-1.91 (m, 1H) 2.85 (d, J=11.49 Hz, 1H) 3.15-3.27 (m, 2H)3.35-3.46 (m, 1H) 4.16-4.26 (m, 1H) 4.87 (d, J=3.42 Hz, 1H) 7.35 (d,J=8.56 Hz, 2H) 7.85 (d, J=9.05 Hz, 2H) 8.00 (d, J=8.07 Hz, 1H) 8.06-8.14(m, 2H) 8.80 (d, J=2.20 Hz, 1H) 8.85 (d, J=1.71 Hz, 1H) 10.17 (s, 1H).

Example 33(S)-6-(3-Hydroxypyrrolidin-1-yl)-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

(S)-5-Bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 33.1, 2.4. g, 5.38 mmol) and pyrimidin-5-ylboronic acid (1.33 g,10.76 mmol) were dissolved in a mixture of DME (15 mL) and EtOH (2.1mL). A solution of 2 M aq. NaHCO₃ (8.07 mL, 16.14 mmol) was added, theRM was flushed with argon, then Pd(PPh₃)₂Cl₂ (0.453 g, 0.645 mmol) wasadded and the RM was stirred under argon at 90° C. for 2 h. Aftercooling to RT, the RM was dissolved in EtOAc and washed with brine. Theorganic phase was dried over Na₂SO₄ and evaporated to dryness underreduced pressure. The residue was purified by flash chromatography(Silica gel column, 200 g, DCM/MeOH from 2% to 5% MeOH). Treatment withSi-Thiol (1 g) in MeOH and a further purification by flashchromatography (RediSep® Silica gel column, EtOAc/MeOH from 0 to 20%MeOH) afforded the title compound as white crystalline solid. HPLC(Condition 4) t_(R)=4.63 min, HPLC Chiral (CHIRALPAK® AD-H, 250×4.6 mm,eluent: EtOH, 0.5 mL/min, UV 210 nm) t_(R)=31.72 min, UPLC-MS (Condition3) t_(R)=0.91 min, m/z=446.2 [M+H]⁺; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm1.67-1.78 (m, 1H) 1.79-1.89 (m, 1H) 2.87 (d, J=11.73 Hz, 1H) 3.21 (m,J=11.10, 4.90 Hz, 2H) 3.37 (m, J=7.40 Hz, 1H) 4.19 (br. s, br. s, 1H)4.87 (d, J=3.52 Hz, 1H) 7.33 (d, J=8.99 Hz, 2H) 7.75-7.89 (m, 2H) 8.08(d, J=2.35 Hz, 1H) 8.70-8.83 (m, 1H) 8.87 (s, 2H) 9.18 (s, 1H) 10.16 (s,1H).

Stage 33.1(S)-5-Bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

5-Bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.2,2.37 g, 6.0 mmol) and (S)-pyrrolidin-3-ol (0.627 g, 7.2 mmol) weredissolved in iPrOH (6 mL). DIPEA (2.1 mL, 12 mmol) was added and the RMmixture was heated at 140° C. for 1 h in a MW vial. After cooling to RT,the RM was dissolved in EtOAc, and washed with 0.5 M HCl and brine. Theorganic phase was dried over Na₂SO₄ and concentrated under reducedpressure until the crystallization began. The mixture was trituratedwith n-pentane, filtered and dried to afford the title compound as abeige crystalline solid. HPLC (Condition 4) t_(R)=5.51 min, UPLC-MS(Condition 3) t_(R)=1.09 min, m/z=448.1 [M+H]⁺; ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 1.74-2.03 (m, 2H) 3.55 (d, J=11.34 Hz, 1H) 3.64-3.74 (m,1H) 3.78-3.89 (m, 2H) 4.33 (br. s, br. s, 1H) 4.97 (d, J=3.13 Hz, 1H)7.33 (d, J=8.99 Hz, 2H) 7.78-7.90 (m, 2H) 8.32 (d, J=1.56 Hz, 1H)8.63-8.72 (m, 1H) 10.20 (s, 1H).

Example 34(S)-2-(3-Hydroxypyrrolidin-1-yl)-6′-methyl-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

(S)-5-Bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 33.1, 60 mg, 0.134 mmol) and (6-methylpyridin-3-yl)boronic acid(36.8 mg, 0.19 mmol) were dissolved in DME (0.5 mL). A solution of 2 Maq. NaHCO₃ (0.2 mL, 0.6 mmol) was added, the RM was flushed with argon,heated to 90° C., and then treated with Pd(PPh₃)₂Cl₂ (9.44 mg, 0.013mmol). The RM was stirred under argon at 90° C. for 2 h in a sealedpressure safe tube. After cooling at RT, the RM was dissolved in EtOAc,and washed with brine. The organic phase was dried over Na₂SO₄ andevaporated to dryness under reduced pressure. The crude product waspurified by flash chromatography (RediSep® Silica gel column, DCM/MeOHfrom 2% to 10% MeOH) and treated with Si-Thiol (50 mg) in MeOH to affordthe title compound as an off-white amorphous solid. HPLC (Condition 4)t_(R)=4.09 min, UPLC-MS (Condition 7) m/z=459.2 [M+H]⁺; ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 1.60-1.75 (m, 1H) 1.76-1.87 (m, 1H) 2.52 (s, 3H) 2.86 (d,J=11.73 Hz, 1H) 3.11-3.24 (m, 2H) 3.27-3.43 (m, 1H) 4.17 (br. s, br. s,1H) 4.83 (br. s, br. s, 1H) 7.28-7.39 (m, 3H) 7.69 (dd, J=7.82, 1.96 Hz,1H) 7.79-7.89 (m, 2H) 7.98 (d, J=2.35 Hz, 1H) 8.48 (d, J=2.35 Hz, 1H)8.73 (d, J=2.35 Hz, 1H) 10.15 (s, 1H).

Example 35(R)-6-(3-Hydroxypyrrolidin-1-yl)-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

5-Bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 35.1,2 g, 4.48 mmol), pyrimidin-5-ylboronic acid (0.666 g, 5.38 mmol),Pd(PPh₃)₂Cl₂ (0.315 g, 0.448 mmol) and Na₂CO₃ (1.425 g, 13.45 mmol) wereadded to a MW vial. The vial was sealed, evacuated/purged with argon,and DME (12.55 mL), water (3.59 mL), EtOH (1.793 mL) were added. The RMwas stirred at 80° C. for 3.5 h, diluted with THF (4 mL), treated withSi-Thiol (Silicycle, 1.27 mmol/g, 1.765 g, 2.241 mmol), filtered and thefiltrate was evaporated off under reduced pressure to give a residuewhich was purified by flash chromatography (RediSep® Silica gel column,120 g, cyclohexane/EtOAc-EtOH+0.1% NH4OH (9:1), from 60% to 90%EtOAc-EtOH+0.1% NH4OH (9:1)). Crystallization from a toluene/EtOHmixture yielded the title compound as a white amorphous solid. HPLCChiral (CHIRALPAK® AD-H, 250×4.6 mm, eluent: EtOH, 0.5 mL/min, UV 210nm) t_(R)=18.58 min, UPLC-MS (condition 1) t_(R)=2.07 min, m/z=446.1[M+H]⁺, m/z=444.2 [M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.70-1.80 (m,1H) 1.81-1.92 (m, 1H) 2.89 (d, J=11.25 Hz, 1H) 3.18-3.28 (m, 2H)3.35-3.44 (m, 1H) 4.22 (br. s, br. s, 1H) 4.89 (d, J=3.42 Hz, 1H) 7.35(d, J=9.05 Hz, 2H) 7.85 (d, J=9.05 Hz, 2H) 8.10 (d, J=2.45 Hz, 1H) 8.80(d, J=2.20 Hz, 1H) 8.89 (s, 2H) 9.20 (s, 1H) 10.17 (s, 1H).

Stage 35.1(R)-5-Bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

(R)-5-Bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 12.2, 2 g, 5.06 mmol) and (R)-pyrrolidin-3-ol (0.529 g, 6.07mmol) in iPrOH (7.78 mL) were added to a MW vial and subjected to MWirradiation at 140° C. for 30 min. The RM was evaporated to drynessunder reduced pressure then extracted from 0.5 M HCl (100 mL) and EtOAc(60 mL). Aq. layer was back extracted with EtOAc (60 mL) and thecombined organic layers washed with HCl 0.5 M, water, dried over MgSO₄and evaporated to dryness under reduced pressure. Trituration of theresidue in cyclohexane/EtOAc mixture and filtration of the solidafforded the title compound as a yellow solid. UPLC-MS (condition 1)t_(R)=2.64 min, m/z=445.9/447.9 [M+H]⁺, m/z=444.0/446.0 [M−H]⁻; ¹H-NMR(400 MHz, DMSO-d₆) δ ppm 1.82-1.91 (m, 1H) 1.91-1.99 (m, 1H) 3.57 (d,J=11.49 Hz, 1H) 3.71 (ddd, J=10.94, 7.89, 3.42 Hz, 1H) 3.81-3.92 (m, 2H)4.31-4.40 (m, 1H) 4.98 (d, J=3.18 Hz, 1H) 7.35 (d, J=8.31 Hz, 2H) 7.85(d, J=9.29 Hz, 2H) 8.34 (d, J=2.20 Hz, 1H) 8.68 (d, J=2.20 Hz, 1H) 10.21(s, 1H).

Example 36(R)-6-(3-Hydroxypyrrolidin-1-yl)-5-(2-methylpyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

(R)-5-Bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 35.1, 60 mg, 0.134 mmol),2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (44.4mg, 0.202 mmol), Pd(PPh₃)₂Cl₂ (9.44 mg, 0.013 mmol) and Na₂CO₃ (42.8 mg,0.403 mmol) were added to a MW vial and treated with DME (570 μL), EtOH(81 μL) and water (163 μL). The vial was sealed, evacuated/purged withargon, and subjected to MW irradiation at 80° C. with stirring for 2 h,diluted with THF (1 mL), treated with Si-Thiol (Silicycle, 1.27 mmol/g,52.9 mg, 0.067 mmol), filtered and the filtrate was evaporated off underreduced pressure to give a residue which was purified by preparativeHPLC (Condition 12, 20% for 0.2 min then 20% to 50% in 12 min) to yieldthe title compound as a white solid. UPLC-MS (condition 1) t_(R)=1.82min, m/z=458.2 [M+H]⁺, m/z=443.2 [M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm1.69-1.80 (m, 1H) 1.79-1.92 (m, 1H) 2.69 (s, 3H) 2.91 (d, J=11.00 Hz,1H) 3.14-3.49 (m, 3H) 4.13-4.28 (m, 1H) 4.83 (br. s, 1H) 7.34 (d, J=8.56Hz, 2H) 7.80-7.91 (m, 2H) 8.05 (d, J=2.45 Hz, 1H) 8.75 (s, 2H) 8.78 (d,J=2.20 Hz, 1H) 10.14 (s, 1H).

Example 37(R)-6-(3-Hydroxypyrrolidin-1-yl)-5-(2-methoxypyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 36 using(R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 35.1) and (6-methoxypyridin-3-yl)boronic acid to afford a whitesolid. UPLC-MS (condition 1) t_(R)=2.24 min, m/z=476.2-477.2 [M+H]⁺,m/z=474.2-475.2 [M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.71-1.79 (m,1H) 1.80-1.91 (m, 1H) 2.96 (d, 1H) 3.21-3.45 (m, 3H) 3.98 (s, 3H)4.20-4.25 (m, 1H) 4.86-4.90 (m, 1H) 7.35 (d, J=8.80 Hz, 2H) 7.85 (d, 2H)8.02 (d, J=2.45 Hz, 1H) 8.67 (s, 2H) 8.77 (d, J=2.45 Hz, 1H) 10.15 (s,1H).

Example 38(R)-5-(2-Aminopyrimidin-5-yl)-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

A mixture of(R)-5-chloro-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 38.1, 50 mg, 0.124 mmol), (2-aminopyrimidin-5-yl)boronic acid (26mg, 0.187 mmol), 2 M Na₂CO₃ (0.124 mL, 0.249 mmol) and DME (2.5 mL) wasflushed with argon and PdCl₂(dppf)(CH₂Cl₂) (10 mg, 0.012 mmol) wasadded. The mixture was subjected to MW irradiation 140° C. for 30 min,passed through a PL-Thiol MP SPE cartridge (StratoSpheres™), thecartridge was washed with MeOH and the solvent was evaporated off underreduced pressure to give a residue which was purified by preparativeLC-MS to afford the title compound. LC-MS (Condition 5) t_(R)=1.53 min,m/z=461.1 [M+H]⁺, m/z=459.1 [M−H]⁻.

Stage 38.1(R)-5-Chloro-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

A mixture of 5,6-dichloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide(prepared from 5,6-dichloronicotinic acid in an analogous fashion tothat described in Stage 12.2, 1.5 g, 4.27 mmol), (R)-pyrrolidin-3-ol(447 mg, 5.13 mmol), iPrOH (10 mL) and DIPEA (1.104 g, 8.54 mmol) weresubjected to MW irradiation at 140° C. for 60 min. The RM was quenchedwith water (100 mL) and extracted with EtOAc (3×100 mL). The combinedorganic extracts were washed with brine (100 mL), dried over MgSO₄,filtered and the filtrate was evaporated off under reduced pressure toafford the title compound as a beige powder. ¹H-NMR (400 MHz, DMSO-d₆) δppm 1.85-1.97 (m, 2H) 3.59 (d, J=12 Hz, 1H) 3.7-3.8 (m, 1H) 3.8-3.95 (m,2H) 4.35-4.40 (m, 1H) 5.00 (s, 1H) 7.35 (d, J=2 Hz, 2H) 7.86 (d, J=2 Hz,2H) 8.17 (s, 1H) 8.66 (s, 1H) 10.22 (s, 1H).

Example 39(R)-2-(3-Hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 36 using(R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 35.1) and pyridin-3-ylboronic acid to afford a yellow solid.UPLC-MS (condition 1) t_(R)=1.82 min, m/z=445.1 [M+H]⁺, m/z=443.2[M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.67-1.77 (m, 1H) 1.83 (dd,J=8.80, 4.40 Hz, 1H) 2.87 (d, J=11.49 Hz, 1H) 3.14-3.26 (m, 2H)3.39-3.45 (m, 1H) 4.18 (d, J=2.45 Hz, 1H) 4.83 (br. s, 1H) 7.34 (d,J=8.31 Hz, 2H) 7.50 (dd, J=7.70, 4.77 Hz, 1H) 7.78-7.90 (m, 3H) 8.03 (d,J=2.20 Hz, 1H) 8.55-8.61 (m, 1H) 8.65 (d, J=1.71 Hz, 1H) 8.77 (d, J=2.45Hz, 1H) 10.17 (s, 1H).

Example 40(R)-2′-(3-Hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-[2,3′-bipyridine]-5′-carboxamide

(R)-6-(3-Hydroxypyrrolidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 40.1, 150 mg, 0.243 mmol), 2-bromopyridine (192 mg, 1.216 mmol),Pd(Ph₃P)₂Cl₂ (17.07 mg, 0.024 mmol) and Na₂CO₃ (77 mg, 0.730 mmol) wereadded to a MW vial and treated with a mixture of DME (1032 μL), water(295 μL) and EtOH (147 μL). The vial was sealed, evacuated/purged withargon and subjected to MW irradiation at 125° C. for 20 min. The RM wasdiluted with DME (2 mL), treated with Si-Thiol (Silicycle, 1.43 mmol/g,102 mg, 0.146 mmol), centrifuged, the supernatant was filtered and thesolvent was evaporated off under reduced pressure to give a residuewhich was purified by flash chromatography (RediSep® Silica gel column,12 g, cyclohexane/EtOAc-EtOH+0.1% NH4OH (9:1), from 25% to 100%EtOAc-EtOH+0.1% NH4OH (9:1)) and further purification by preparativeHPLC (Condition 13, from 5% to 100% in 14 min) yielded the titlecompound as a yellow solid. UPLC-MS (condition 1) t_(R)=1.85 min,m/z=445.2 [M+H]⁺, m/z=443.2 [M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm1.65-1.78 (m, 1H) 1.79-1.94 (m, 1H) 2.85 (d, J=11.49 Hz, 1H) 3.13-3.28(m, 2H) 3.36-3.50 (m, 1H) 4.19 (d, J=2.20 Hz, 1H) 4.83 (d, J=3.18 Hz,1H) 7.24-7.44 (m, 3H) 7.53 (d, J=7.82 Hz, 1H) 7.80-7.97 (m, 3H) 8.12 (d,J=2.20 Hz, 1H) 8.66 (dd, J=4.89, 0.73 Hz, 1H) 8.78 (d, J=2.45 Hz, 1H)10.20 (s, 1H).

Stage 40.1(R)-6-(3-Hydroxypyrrolidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

(R)-5-Bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 35.1, 376 mg, 0.843 mmol), bis(pinacolato)diboron (856 mg, 3.37mmol), SPhos (25.9 mg, 0.063 mmol), Pd(OAc)₂ (5.68 mg, 0.025 mmol) andfinely ground K₃PO₄ (537 mg, 2.53 mmol) were added to a MW vial, whichwas sealed and evacuated/purged with argon. Dioxane (3.371 mL) was addedand the RM was stirred at 50° C. for 3 days. A second portion ofbis(pinacolato)diboron (428 mg, 1.685 mmol) was then added and thereaction was stirred at 50° C. for 16 h and then at 65° C. overnight.Water (30 mL) was added and the mixture was extracted with EtOAc/TBME(1:1). The combined extracts were washed with brine, dried over Na₂SO₄and the solvent was evaporated off under reduced pressure to give acrude product which was purified by flash chromatography (RediSep®Silica gel column, 24 g, cyclohexane/EtOAc-EtOH+0.1% NH4OH (9:1), from20% to 70% EtOAc-EtOH+0.1% NH4OH (9:1)) to afford the title compound asa grey solid. UPLC-MS (condition 1) t_(R)=2.42 min, m/z=493.1 [M+H]⁺,m/z=491.1 [M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.33 (d, J=5.38 Hz,12H) 1.80-1.93 (m, 1H) 1.99 (s, 1H) 3.27 (s, 1H) 3.40-3.59 (m, 1H)3.59-3.78 (m, 2H) 4.37 (br. s, 1H) 4.96 (d, J=3.18 Hz, 1H) 7.34 (d,J=8.56 Hz, 2H) 7.80-7.90 (m, 2H) 8.18 (d, J=2.69 Hz, 1H) 8.76 (d, J=2.69Hz, 1H) 10.19 (s, 1H).

Example 41(R)-2-(3-Hydroxypyrrolidin-1-yl)-6′-methyl-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 36 using(R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 35.1) and (6-methylpyridin-3-yl)boronic acid to afford a whitesolid. UPLC-MS (condition 1) t_(R)=1.60 min, m/z=459.0 [M+H]⁺, m/z=457.2[M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.73 (dd, J=8.07, 3.91 Hz, 1H)1.77-1.89 (m, 1H) 2.55 (s, 3H) 2.88 (d, J=11.74 Hz, 1H) 3.17-3.27 (m,2H) 3.42 (br. s, 1H) 4.19 (br. s, 1H) 4.84 (br. s, 1H) 7.34 (d, J=8.31Hz, 2H) 7.39 (d, J=7.83 Hz, 1H) 7.75 (dd, J=7.95, 1.83 Hz, 1H) 7.85 (d,2H) 8.00 (d, J=2.45 Hz, 1H) 8.52 (d, J=1.96 Hz, 1H) 8.75 (d, J=2.20 Hz,1H) 10.16 (s, 1H).

Example 42(R)-6′-(Hydroxymethyl)-2-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

(R)-5-Bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 35.1, 89 mg, 0.2 mmol) and (6-(hydroxymethyl)pyridin-3-yl)boronicacid (61.2 mg, 0.4 mmol) were dissolved in DME (0.8 mL). A solution of 2M NaHCO₃ (0.3 mL, 0.6 mmol) was added, the RM was flushed with argon,heated to 90° C. and treated with Pd(PPh₃)₂Cl₂ (14.0 mg, 0.02 mmol). TheRM was stirred under argon at 95° C. for 2 h in a sealed pressure safetube. After cooling to RT, the RM was dissolved in EtOAc and washed withbrine. The organic phase was dried over Na₂SO₄ and evaporated to drynessunder reduced pressure. The residue was diluted in MeOH, treated withSi-Thiol (100 mg), the resin was filtered off and the solvent wasevaporated off under reduced pressure to give a residue which waspurified by flash chromatography (Silica gel column, EtOAc/MeOH, from 0to 20% MeOH) afforded the title compound as an off-white amorphoussolid. HPLC (Condition 4) t_(R)=4 min, UPLC-MS (Condition 3) t_(R)=0.87min, m/z=475.3 [M+H]⁺; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.63-1.76 (m, 1H)1.77-1.86 (m, 1H) 2.86 (d, J=11.34 Hz, 1H) 3.11-3.26 (m, 2H) 3.33-3.43(m, 1H) 4.12-4.22 (m, 1H) 4.61 (d, J=5.87 Hz, 2H) 4.84 (d, J=3.13 Hz,1H) 5.47 (t, J=5.87 Hz, 1H) 7.33 (d, J=8.99 Hz, 2H) 7.53 (d, J=8.21 Hz,1H) 7.74-7.88 (m, 3H) 8.00 (d, J=2.35 Hz, 1H) 8.51 (d, J=2.35 Hz, 1H)8.74 (d, J=2.35 Hz, 1H) 10.15 (s, 1H).

Example 43(R)-2-(3-Hydroxypyrrolidin-1-yl)-2′-methyl-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 36 using(R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 35.1) and (2-methylpyridin-3-yl)boronic acid to afford a whitesolid. UPLC-MS (condition 1) t_(R)=1.71 min, m/z=459.0 [M+H]⁺, m/z=547.2[M−H]⁻.

Example 44(R)-2-(3-Hydroxypyrrolidin-1-yl)-5′-methyl-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 36 using(R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 35.1) and (5-methylpyridin-3-yl)boronic acid to afford a whitesolid. UPLC-MS (condition 1) t_(R)=1.87 min, m/z=459.1 [M+H]⁺, m/z=457.2[M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.66-1.79 (m, 1H) 1.85 (d,J=9.05 Hz, 1H) 2.39 (s, 3H) 2.88 (d, J=11.98 Hz, 1H) 3.15-3.30 (m, 2H)3.37-3.49 (m, 1H) 4.15-4.25 (m, 0H) 4.83 (br. s, 0H) 7.35 (d, J=8.31 Hz,2H) 7.67 (s, 1H) 7.85 (d, 2H) 8.02 (d, J=2.45 Hz, 1H) 8.39-8.49 (m, 2H)8.77 (d, J=2.45 Hz, 1H) 10.15 (s, 1H).

Example 45(R)-5′-Fluoro-2-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 36 using(R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 35.1) and (5-fluoropyridin-3-yl)boronic acid to afford a whitesolid. UPLC-MS (condition 1) t_(R)=2.39 min, m/z=463.1 [M+H]⁺, m/z=461.2[M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.69-1.79 (m, 1H) 1.79-1.91 (m,1H) 2.88 (d, J=11.00 Hz, 1H) 3.17-3.27 (m, 2H) 3.36-3.45 (m, 1H) 4.21(br. s, 1H) 4.87 (br. s, 1H) 7.35 (d, J=8.56 Hz, 2H) 7.79-7.90 (m, 3H)8.08 (d, J=2.20 Hz, 1H) 8.51 (s, 1H) 8.60 (d, J=2.69 Hz, 1H) 8.78 (d,J=2.45 Hz, 1H) 10.17 (s, 1H).

Example 46(R)-2′-Fluoro-2-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

A mixture of(R)-5-chloro-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 38.1, 50 mg, 0.124 mmol), (2-fluoropyridin-3-yl)boronic acid (26mg, 0.187 mmol), 2 M Na₂CO₃ (0.124 mL, 0.249 mmol) and DME (2.5 mL) wasflushed with argon. PdCl₂(dppf)(CH₂Cl₂) (10 mg, 0.012 mmol) was addedand the mixture was subjected to MW irradiation 140° C. for 30 min,filtered through a PL-Thiol MP SPE cartridge (StratoSpheres™, 6 mL), thecartridge was washed with MeOH and the solvent was evaporated off underreduced pressure to give a residue which was purified by preparativeLC-MS to afford the title compound. LC-MS (Condition 6) t_(R)=1.71 min,m/z=463.0 [M+H]⁺.

Example 47(R)-6′-Fluoro-2-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 54 using(R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 35.1) and (6-fluoropyridin-3-yl)boronic acid to afford a whitesolid. LC-MS (Condition 2) t_(R)=1.91 min, m/z=463.2-464.2 [M+H]⁺,m/z=461 [M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.69-1.78 (m, 1H)1.79-1.89 (m, 1H) 2.89 (d, J=11.49 Hz, 1H) 3.17-3.28 (m, 2H) 3.34-3.44(m, 1H) 4.20 (s, 1H) 4.85 (s, 1H) 7.29 (dd, J=8.44, 2.57 Hz, 1H) 7.35(d, J=8.80 Hz, 2H) 7.85 (d, J=9.29 Hz, 2H) 7.98-8.05 (m, 2H) 8.30 (d,J=1.96 Hz, 1H) 8.77 (d, J=2.20 Hz, 1H) 10.16 (s, 1H).

Example 48(R)-4′-Fluoro-2-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 7 using(R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 35.1) and4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine toafford a solid. UPLC-MS (Condition 3), t_(R)=0.97 min, m/z=463.3 [M+H]⁺;¹H-NMR (400 MHz, DMSO-d6), δ ppm 1.66-1.76 (m, 1H) 1.77-1.89 (m, 1H)2.87-2.97 (m, 1H) 3.14-3.21 (m, 1H) 3.30 (s, 2H) 4.14-4.23 (m, 1H)4.82-4.92 (m, 1H) 7.33 (d, J=8.99 Hz, 2H) 7.41-7.49 (m, 1H) 7.83 (d,J=8.99 Hz, 2H) 8.03 (d, J=2.35 Hz, 1H) 8.61-8.67 (m, 1H) 8.68-8.77 (m,1H) 8.79 (d, J=2.35 Hz, 1H) 10.15 (s, 1H).

Example 49(R)-2′,5′-Difluoro-2-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 7 using(R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 35.1) and2,5-difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine toafford a solid. UPLC-MS (Condition 3), t_(R)=1.05 min, m/z=481.3 [M+H]⁺;¹H-NMR (400 MHz, DMSO-d6), δ ppm 1.78 (br. s, 1H) 1.87 (br. s, 1H) 2.97(br. s, 1H) 3.17-3.29 (m, 2H) 3.42 (dd, J=16.03, 7.04 Hz, 1H) 4.23 (br.s, 1H) 4.91 (br. s, 1H) 7.35 (m, J=8.60 Hz, 2H) 7.50 (br. s, 1H) 7.85(m, J=8.99 Hz, 2H) 8.05-8.13 (m, 1H) 8.28-8.39 (m, 1H) 8.74-8.86 (m, 1H)10.18 (s, 1H).

Example 50(R)-5′-Chloro-2-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 54 using(R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 35.1) and (5-chloropyridin-3-yl)boronic acid to afford a whitesolid. UPLC-MS (condition 1) t_(R)=2.61 min, m/z=479.1-481.0 [M+H]⁺,m/z=477.1-479.1 [M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.70-1.79 (m,1H) 1.80-1.91 (m, 1H) 2.89 (d, 1H) 3.18-3.28 (m, 2H) 3.35-3.44 (m, 1H)4.18-4.24 (m, 1H) 4.87 (d, J=3.42 Hz, 1H) 7.35 (d, J=8.80 Hz, 2H)7.83-7.88 (m, 2H) 8.03 (t, J=1.96 Hz, 1H) 8.08 (d, J=2.20 Hz, 1H) 8.58(d, J=1.71 Hz, 1H) 8.64 (d, J=2.45 Hz, 1H) 8.78 (d, J=2.45 Hz, 1H) 10.16(s, 1H).

Example 51(R)-2-(3-Hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-6′-(trifluoromethyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 54 using(R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 35.1) and (6-(trifluoromethyl)pyridin-3-yl)boronic acid to afforda white solid. UPLC-MS (condition 1) t_(R)=2.80 min, m/z=513.0 [M+H]⁺,m/z=511.0 [M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.69-1.80 (m, 1H)1.79-1.91 (m, 1H) 2.85 (d, J=11.49 Hz, 1H) 3.16-3.27 (m, 2H) 3.40 (td,J=9.84, 7.21 Hz, 1H) 4.21 (br. s, 1H) 4.87 (br. s, 1H) 7.35 (d, J=8.31Hz, 2H) 7.81-7.89 (m, 2H) 8.01 (d, J=7.58 Hz, 1H) 8.08-8.13 (m, J=8.31,2.45, 2.45, 2.45 Hz, 2H) 8.80 (d, J=2.20 Hz, 1H) 8.85 (d, J=1.96 Hz, 1H)10.18 (s, 1H).

Example 52(R)-5′-Fluoro-2-(3-hydroxypyrrolidin-1-yl)-6′-methyl-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

(R)-6′-Chloro-5′-fluoro-2-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide(Example 53, 139 mg, 0.28 mmol) and trimethyl-boroxine (34.4 mg, 0.274mmol) were dissolved in dioxane (1.5 mL). K₂CO₃ (104 mg, 0.756 mmol) wasadded, the RM was flushed with argon and Pd(PPh₃)₄ (32.4 mg, 0.028 mmol)was added. The RM was heated overnight at 110° C. After cooling to RT,the RM was dissolved in EtOAc treated with water, and extracted withEtOAc. The combined extracts were dried over Na₂SO₄ and evaporated todryness under reduced pressure. The crude product was purified by flashchromatography (RediSep® Silica gel column, DCM/MeOH from 2% to 5%MeOH). Further purification by reverse phase chromatography (MPLC,Lichroprep 15-25 μm column, water+0.1% formic acid/MeCN+0.1% formicacid, gradient 10 to 41% MeCN+0.1% formic acid). The combined purefractions were neutralized with NaHCO₃ and extracted with EtOAc. Thecombined organic phases were dried over Na₂SO₄ and evaporated. Theresidue was dissolved in MeOH and evaporated under reduced pressure toafford the title compound as an off-white amorphous solid. HPLC(Condition 4) t_(R)=5.16 min, UPLC-MS (Condition 7) m/z=477.2 [M+H]⁺;¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.65-1.76 (m, 1H) 1.78-1.88 (m, 1H)2.42-2.56 (m, 3H) 2.87 (d, J=11.73 Hz, 1H) 3.14-3.28 (m, 2H) 3.33-3.43(m, 1H) 4.18 (br. s, 1H) 4.84 (d, J=3.52 Hz, 1H) 7.33 (d, J=8.99 Hz, 2H)7.71 (dd, J=10.17, 1.56 Hz, 1H) 7.79-7.90 (m, 2H) 8.02 (d, J=2.35 Hz,1H) 8.34 (s, 1H) 8.75 (d, J=2.74 Hz, 1H) 10.15 (s, 1H).

Example 53(R)-6′-Chloro-5′-fluoro-2-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

(R)-5-Bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 35.1, 300 mg, 0.672 mmol) and2-chloro-3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(346 mg, 1.345 mmol) were dissolved in DME (2.7 mL). A solution of 2 MNaHCO₃ (1.01 mL, 2.03 mmol) was added, the RM was flushed with argon andPd(PPh₃)₂Cl₂ (56.6 mg, 0.081 mmol) was added. The RM was stirred underargon at 95° C. for 2 h in a capped pressure safe tube. After cooling toRT, the RM was dissolved in EtOAc, and washed with brine. The organicphase was dried over Na₂SO₄ and evaporated to dryness under reducedpressure. The crude product was purified by flash chromatography(RediSep® Silica gel column, DCM/MeOH from 2% to 5% MeOH), followed by asecond purification (RediSep® Silica gel column, n-hexane/EtOAc, 50 to100% EtOAc) and treatment with Si-Thiol (200 mg) in MeOH to afford thetitle compound as a white powder. HPLC (Condition 4) t_(R)=5.63 min,UPLC-MS (Condition 7) m/z=497.1 [M+H]⁺; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm1.65-1.80 (m, 1H) 1.80-1.91 (m, 1H) 2.87 (d, J=10.56 Hz, 1H) 3.18-3.28(m, 2H) 3.33-3.50 (m, 1H) 4.20 (br. s, 1H) 4.86 (d, J=3.52 Hz, 1H) 7.34(d, J=8.99 Hz, 2H) 7.84 (d, J=8.99 Hz, 2H) 7.99-8.11 (m, 2H) 8.34 (s,1H) 8.77 (d, J=2.35 Hz, 1H) 10.16 (s, 1H).

Example 54(R)-5′-Cyano-2-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

(R)-5-Bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 35.1, 200 mg, 0.448 mmol),5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile (206 mg,0.896 mmol), Pd(PPh₃)₂Cl₂ (31.5 mg, 0.045 mmol) and Na₂CO₃ (143 mg,1.345 mmol) were added to a MW vial and treated with a mixture of DME(1.902 mL), water (543 μL) and EtOH (272 μL). The vial was sealed,evacuated/purged with argon and then the RM was subjected to MWirradiation at 120° C. for 10 min, then cooled to RT and finally treatedwith Si-Thiol (1.27 mmol/g, 176 mg, 0.224 mmol) overnight. The RM wasfiltered and the solvent was evaporated off under reduced pressure togive a residue which was purified by preparative HPLC (Condition 12, 25%for 0.2 min then 25% to 55% in 14 min.) to yield the title compound as awhite solid. UPLC-MS (condition 1) t_(R)=2.30 min, m/z=470.0-471.0[M+H]⁺, m/z=468.0-469.0 [M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm1.70-1.79 (m, 1H) 1.80-1.92 (m, 1H) 2.86 (d, J=11.25 Hz, 1H) 3.16-3.27(m, 2H) 3.34-3.44 (m, 1H) 4.17-4.24 (m, 1H) 4.70-5.04 (m, 1H) 7.35 (d,J=8.80 Hz, 2H) 7.82-7.88 (m, 2H) 8.09 (d, J=2.45 Hz, 1H) 8.40 (t, J=2.08Hz, 1H) 8.79 (d, J=2.20 Hz, 1H) 8.90 (d, J=1.96 Hz, 1H) 9.02 (d, J=1.96Hz, 1H) 10.17 (s, 1H).

Example 55(R)-2-(3-hydroxypyrrolidin-1-yl)-5′-methoxy-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 54 using(R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 35.1) and3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine toafford a white solid. UPLC-MS (condition 1) t_(R)=2.10 min, m/z=475.2[M+H]⁺, m/z=473.2 [M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.67-1.79 (m,1H) 1.79-1.92 (m, 1H) 2.91 (d, J=11.25 Hz, 1H) 3.19-3.27 (m, 2H)3.33-3.47 (m, 1H) 3.89 (s, 3H) 4.16-4.25 (m, 1H) 4.83 (d, J=3.42 Hz, 1H)7.34 (d, J=8.80 Hz, 2H) 7.41 (d, J=1.96 Hz, 1H) 7.86 (d, J=9.05 Hz, 2H)8.04 (d, J=2.45 Hz, 1H) 8.21 (d, J=1.47 Hz, 1H) 8.30 (d, J=2.69 Hz, 1H)8.76 (d, J=2.20 Hz, 1H) 10.15 (s, 1H).

Example 56(R)-2-(3-hydroxypyrrolidin-1-yl)-6′-methoxy-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

(R)-5-Bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 35.1, 60 mg, 0.134 mmol), (6-methoxypyridin-3-yl)boronic acid(25.2 mg, 0.161 mmol), Pd₂(dba)₃ (2.463 mg, 2.69 μmol),2-diclyclohexylphosphino-2′,4′,6′-triisoprophylbiphenyl (2.56 mg, 5.38μmol) and K₃PO₄ (86 mg, 0.403 mmol) were added to a MW vial. The vialwas sealed, evacuated/purged with argon, and BuOH (269 μL) was added.The RM was stirred at 100° C. for 16 h, diluted with THF (1 mL), treatedwith Si-Thiol (Silicycle, 1.27 mmol/g, 52.9 mg, 0.067 mmol), filteredand the filtrate was evaporated off under reduced pressure to give aresidue which was purified by preparative HPLC (Condition 12, from 30%to 60% in 12 min.) to afford the title compound as a white solid.UPLC-MS (condition 1) t_(R)=2.36 min, m/z=475.2 [M+H]⁺, m/z=473.2[M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.68-1.78 (m, 1H) 1.77-1.90 (m,1H) 2.93 (d, J=11.74 Hz, 1H) 3.18-3.26 (m, 2H) 3.35-3.46 (m, 1H) 3.91(s, 3H) 4.20 (br. s, 1H) 4.83 (d, J=3.42 Hz, 1H) 6.91 (d, J=8.56 Hz, 1H)7.34 (d, J=8.56 Hz, 2H) 7.72 (dd, J=8.56, 2.45 Hz, 1H) 7.86 (d, J=9.05Hz, 2H) 7.97 (d, J=2.20 Hz, 1H) 8.21 (d, J=2.45 Hz, 1H) 8.74 (d, J=2.20Hz, 1H) 10.14 (s, 1H).

Example 57(R)-6-(3-Hydroxypyrrolidin-1-yl)-5-phenyl-N-(4-(trifluoromethoxy)phenyl)nicotinamide

(R)-5-Bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 35.1, 89.0 mg) and phenylboronic acid (48.8 mg) were dissolved inDME (0.8 mL). A solution of 2M NaHCO₃ (0.3 mL, 0.6 mmol) was added, theRM was flushed with argon, heated to 90° C., and treated withPd(PPh₃)₂Cl₂ (14.0 mg, 0.02 mmol). The RM was stirred under argon at 95°C. for 2 h in a capped pressure safe tube. After cooling at RT, the RMwas dissolved in EtOAc and washed with brine. The organic phase wasdried over Na₂SO₄ and evaporated to dryness under reduced pressure. Thecrude product was purified by flash chromatography (RediSep® Silica gelcolumn, DCM/MeOH from 2% to 5% MeOH) and treated with Si-Thiol (80 mg)in MeOH to afford the title compound as an off-white powder. HPLC(Condition 4) t_(R)=5.09 min, UPLC-MS (Condition 3) t_(R)=1.14 min,m/z=444.2 [M+H]⁺; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.62-1.73 (m, 1H)1.74-1.85 (m, 1H) 2.85 (d, J=11.34 Hz, 1H) 3.10-3.26 (m, 2H) 3.32-3.45(m, 1H) 4.15 (m, J=2.30 Hz, 1H) 4.80 (d, J=3.13 Hz, 1H) 7.25-7.51 (m,7H) 7.78-7.88 (m, 2H) 7.96 (d, J=2.35 Hz, 1H) 8.72 (d, J=2.30 Hz, 1H)10.15 (s, 1H).

Example 58(R)-5-(3-Fluorophenyl)-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 57 using(R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 35.1) and (3-fluorophenyl)boronic acid to afford an off-whitesolid. HPLC (Condition 4) t_(R)=5.48 min, UPLC-MS (Condition 3)t_(R)=1.17 min, m/z=462.2 [M+H]⁺; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.72(m, J=3.90 Hz, 1H) 1.77-1.89 (m, 1H) 2.86 (d, J=11.34 Hz, 1H) 3.12-3.27(m, 2H) 3.40 (m, J=7.40 Hz, 1H) 4.09-4.22 (m, 1H) 4.82 (d, J=3.52 Hz,1H) 7.15-7.28 (m, 3H) 7.34 (d, J=1.00 Hz, 2H) 7.41-7.53 (m, 1H)7.77-7.90 (m, 2H) 7.99 (d, J=2.30 Hz, 1H) 8.73 (d, J=2.35 Hz, 1H) 10.15(s, 1H).

Example 59(R)-5-(3-(Hydroxymethyl)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 57 using(R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 35.1) and (3-(hydroxymethyl)phenyl)boronic acid to afford ayellow foam. HPLC (Condition 4) t_(R)=4.57 min, UPLC-MS (Condition 3)t_(R)=0.99 min, m/z=474.4 [M+H]⁺; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm1.62-1.73 (m, 1H) 1.80 (m, J=8.60 Hz, 1H) 2.85 (d, J=11.73 Hz, 1H)3.12-3.26 (m, 2H) 3.34-3.47 (m, 1H) 4.09-4.19 (m, 1H) 4.55 (d, J=5.47Hz, 2H) 4.80 (d, J=3.52 Hz, 1H) 5.24 (t, J=5.67 Hz, 1H) 7.22 (d, J=7.43Hz, 1H) 7.27-7.43 (m, 5H) 7.79-7.90 (m, 2H) 7.94 (d, J=2.35 Hz, 1H) 8.71(d, J=2.35 Hz, 1H) 10.16 (s, 1H).

Example 60(R)-5-(3-Fluoro-5-(2-hydroxypropan-2-yl)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 53 using(R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 35.1) and2-(3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-oland to afford a yellow resin. HPLC (Condition 4) t_(R)=5.18 min, UPLC-MS(Condition 3) t_(R)=1.10 min, m/z=520.3 [M+H]⁺; ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 1.43 (d, J=1.96 Hz, 6H) 1.65-1.75 (m, 1H) 1.76-1.89 (m,1H) 2.86 (d, J=10.95 Hz, 1H) 3.13-3.28 (m, 2H) 3.34-3.50 (m, 1H)4.03-4.22 (m, 1H) 4.82 (d, J=2.74 Hz, 1H) 5.19 (d, J=0.78 Hz, 1H) 7.09(d, J=9.38 Hz, 1H) 7.18-7.28 (m, 2H) 7.33 (d, J=8.99 Hz, 2H) 7.77-7.88(m, 2H) 7.98 (m, J=2.30, 0.80 Hz, 1H) 8.67-8.76 (m, 1H) 10.16 (s, 1H).

Example 61(R)-5-(3,5-Difluorophenyl)-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 57 using(R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 35.1) and (3,5-difluorophenyl)boronic acid. HPLC (Condition 4)t_(R)=5.71 min, UPLC-MS (Condition 3) t_(R)=1.20 min, m/z=480.2 [M+H]⁺;¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.67-1.76 (m, 1H) 1.79-1.91 (m, 1H) 2.88(d, J=11.73 Hz, 1H) 3.16-3.28 (m, 2H) 3.42 (m, J=7.00 Hz, 1H) 4.20 (m,J=2.00 Hz, 1H) 4.85 (d, J=3.52 Hz, 1H) 7.15 (dd, J=8.21, 1.95 Hz, 2H)7.21-7.29 (m, 1H) 7.33 (d, J=8.99 Hz, 2H) 7.78-7.90 (m, 2H) 8.02 (d,J=2.35 Hz, 1H) 8.74 (d, J=2.35 Hz, 1H) 10.15 (s, 1H).

Example 62 (R)-Methyl3-fluoro-5-(2-(3-hydroxypyrrolidin-1-yl)-5-((4-(trifluoromethoxy)phenyl)carbamoyl)pyridin-3-yl)benzoate

The title compound was prepared in an analogous fashion to thatdescribed in Example 35 using(R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 35.1) and (3-fluoro-5-(methoxycarbonyl)phenyl)boronic acid toafford a white solid. UPLC-MS (Condition 3), t_(R)=1.18 min, m/z=520.2[M+H]⁺; ¹H-NMR (400 MHz, DMSO-d6), δ ppm 1.67-1.75 (m, 1H) 1.77-1.89 (m,1H) 2.81-2.90 (m, 1H) 3.13-3.27 (m, 2H) 3.33-3.45 (m, 1H) 3.88 (s, 3H)4.13-4.20 (m, 1H) 4.82 (d, J=1.00 Hz, 1H) 7.33 (d, J=8.60 Hz, 2H)7.54-7.63 (m, 1H) 7.65-7.73 (m, 1H) 7.74-7.79 (m, 1H) 7.84 (d, J=9.38Hz, 2H) 8.03 (d, J=2.35 Hz, 1H) 8.75 (d, J=2.35 Hz, 1H) 10.17 (s, 1H).

Example 63(R)-6-(3-Hydroxypyrrolidin-1-yl)-5-(isoquinolin-7-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

A mixture of(R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 35.1, 60 mg, 0.134 mmol), isoquinolin-7-ylboronic acid (35 mg,0.202 mmol), 2 M Na₂CO₃ (0.134 mL) and DME (4 mL) was flushed withargon. PdCl₂(dppf)(CH₂Cl₂) (11 mg, 0.013 mmol) was added and the mixturewas subjected to MW irradiation at 140° C. for 30 min. The RM wasfiltered through a PL-Thiol MP SPE cartridge (StratoSpheres™, 6 mL), thecartridge was washed with MeOH and the solvent was evaporated off underreduced pressure to give a residue which was purified by preparativeLC-MS to afford the title compound as a beige powder. LC-MS (Condition6) t_(R)=1.33 min, m/z=495.1 [M+H]⁺.

Example 64(R)-6-(3-Hydroxypyrrolidin-1-yl)-5-(quinoxalin-6-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 46 using(R)-5-chloro-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 38.1) and quinoxalin-6-ylboronic acid. LC-MS (Condition 6)t_(R)=1.64 min, m/z=496.0 [M+H]⁺.

Example 65(S)-6-(3-Hydroxy-3-methylpyrrolidin-1-yl)-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

(S)-5-Bromo-6-(3-hydroxy-3-methylpyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 65.1, 60 mg, 0.130 mmol), pyrimidin-5-ylboronic acid (32.3 mg,0.261 mmol), Pd(PPh₃)₂Cl₂ (9.15 mg, 0.013 mmol) and Na₂CO₃ (41.5 mg,0.391 mmol) were added to a MW vial and treated with a mixture of DME(553 μL), water (158 μL) and EtOH (79 μL). The vial was sealed,evacuated/purged with argon and was subjected to MW irradiation at 120°C. for 10 min. The RM was diluted with DME (2 mL), treated with Si-Thiol(1.44 mmol/g, 45.3 mg, 0.065 mmol), centrifuged, the supernatant wasfiltered and the solvent was evaporated off under reduced pressure togive a residue which was purified by preparative SFC (Column Silica,from 23% to 28% in 6 min.) to yield the title compound as a whiteamorphous solid. UPLC-MS (Condition 3) t_(R)=0.94 min, m/z=460.4 [M+H]⁺,m/z=458.3 [M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.20 (s, 3H) 1.66-1.84(m, 2H) 2.95 (d, J=11.80 Hz, 1H) 3.02 (d, J=11.17 Hz, 1H) 3.17-3.26 (m,1H) 3.37-3.47 (m, 1H) 4.75 (s, 1H) 7.35 (d, J=8.53 Hz, 2H) 7.85 (d,J=9.16 Hz, 2H) 8.10 (d, J=2.38 Hz, 1H) 8.78 (d, J=2.13 Hz, 1H) 8.89 (s,2H) 9.16-9.24 (m, 1H) 10.18 (s, 1H).

Stage 65.1(S)-5-Bromo-6-(3-hydroxy-3-methylpyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

The title compound was obtained after chiral separation (preparativeHPLC, Chiralcel OD 20 μm 00CM-EK002, 50×5 cm, mobile phase:n-heptane/EtOH (90:10)formic acid, flow rate: 50 mL/min) of racemic5-bromo-6-(3-hydroxy-3-methylpyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 65.2) (2.18 g, 4.74 mmol) as a white solid. UPLC-MS (Condition 3)t_(R)=1.14 min, m/z=460.3/462.3 [M+H]⁺, m/z=458.1/460.1 [M−H]⁻; ¹H-NMR(400 MHz, DMSO-d₆) δ ppm 1.32 (s, 3H) 1.74-1.91 (m, 2H) 3.60 (d, J=11.32Hz, 1H) 3.66 (d, J=11.32 Hz, 1H) 3.69-3.74 (m, 1H) 3.86-3.95 (m, 1H)4.79 (s, 1H) 7.33 (d, J=8.59 Hz, 2H) 7.79-7.87 (m, 2H) 8.31 (d, J=1.95Hz, 1H) 8.65 (d, J=1.95 Hz, 1H) 10.20 (s, 1H). Chiral HPLC: Column:Chiralcel OD-H 5 μm, 4.6×250 mm, eluent n-heptane/EtOH (9:1), flow at1.1 mL/min, t_(R)=11.29 min, ee=99.0% (UV-210 nm).

Stage 65.25-Bromo-6-(3-hydroxy-3-methylpyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Stage 12.1 using5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.2)and 3-methylpyrrolidin-3-ol hydrochloride to afford a white solid.UPLC-MS (condition 1) t_(R)=2.79 min, m/z=460.9/461.9 [M+H]⁺,m/z=458.0/460 [M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.34 (s, 3H)1.76-1.93 (m, 2H) 3.63 (d, 1H) 3.68 (d, 1H) 3.70-3.76 (m, 1H) 3.88-3.97(m, 1H) 4.82 (s, 1H) 7.35 (d, J=8.31 Hz, 2H) 7.85 (d, J=9.05 Hz, 2H)8.33 (d, J=2.20 Hz, 1H) 8.67 (d, J=2.20 Hz, 1H) 10.22 (s, 1H).

Example 66(R)-6-(3-Hydroxy-3-methylpyrrolidin-1-yl)-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

(R)-5-Bromo-6-(3-hydroxy-3-methylpyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 66.1, 60 mg, 0.130 mmol), pyrimidin-5-ylboronic acid (32.3 mg,0.261 mmol), Pd(PPh₃)₂Cl₂ (9.15 mg, 0.013 mmol) and Na₂CO₃ (41.5 mg,0.391 mmol) were added to a MW vial and treated with a mixture of DME(553 μL), water (158 μL) and EtOH (79 μL). The vial was sealed,evacuated/purged with argon and subjected to MW irradiation at 120° C.for 10 min. The RM was diluted with DME (2 mL), treated with Si-Thiol(Silicycle, 1.44 mmol/g, 45.3 mg, 0.065 mmol), centrifuged, thesupernatant was filtered and the solvent was evaporated off underreduced pressure to give a residue which was purified by preparative SFC(Column Silica, from 23% to 28% in 6 min) to yield the title compound asa white solid. UPLC-MS (Condition 3) t_(R)=0.94 min, m/z=460.4 [M+H]⁺,m/z=458.3 [M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.20 (s, 3H) 1.67-1.83(m, 2H) 2.96 (d, J=10.54 Hz, 1H) 3.03 (d, J=10.54 Hz, 1H) 3.18-3.26 (m,1H) 3.38-3.47 (m, 1H) 4.75 (s, 1H) 7.36 (d, J=8.28 Hz, 2H) 7.82-7.90 (m,2H) 8.10 (d, J=2.38 Hz, 1H) 8.79 (d, J=2.38 Hz, 1H) 8.89 (s, 2H) 9.20(s, 1H) 10.19 (s, 1H).

Stage 66.1(R)-5-Bromo-6-(3-hydroxy-3-methylpyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

The title compound was obtained after chiral separation (preparativeHPLC, Chiralcel OD 20 μm 00CM-EK002, 50×5 cm, mobile phase:n-heptane/EtOH (90:10)formic acid, flow rate: 50 mL/min) of racemic5-bromo-6-(3-hydroxy-3-methylpyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 65.2) (2.18 g, 4.74 mmol) as a white solid. UPLC-MS (Condition 3)t_(R)=1.14 min, m/z=460.3/462.3 [M+H]⁺, m/z=458.1/460.1 [M−H]⁻; ¹H-NMR(400 MHz, DMSO-d₆) δ ppm 1.32 (s, 3H) 1.71-1.95 (m, 2H) 3.60 (d, J=10.93Hz, 1H) 3.66 (d, J=10.93 Hz, 1H) 3.69-3.74 (m, 1H) 3.85-3.95 (m, 1H)4.79 (s, 1H) 7.33 (d, J=8.59 Hz, 2H) 7.80-7.86 (m, 2H) 8.31 (d, J=2.34Hz, 1H) 8.65 (d, J=1.95 Hz, 1H) 10.20 (s, 1H). Chiral HPLC: Column:Chiralcel OD-H 5 μm, 4.6×250 mm, eluent n-heptane/EtOH (9:1), flow at1.1 mL/min, t_(R)=16.66 min, ee=99.4% (UV-210 nm).

Example 675-(Pyrimidin-5-yl)-6-(pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 66 using5-bromo-6-(pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 67.1) and pyrimidin-5-ylboronic acid to afford a white solid.UPLC-MS (Condition 3) t_(R)=1.07 min, m/z=430.4 [M+H]⁺, m/z=428.3[M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.68-1.94 (m, 4H) 3.15 (t,J=6.15 Hz, 4H) 7.37 (d, J=8.78 Hz, 2H) 7.86 (d, J=8.91 Hz, 2H) 8.11 (d,J=2.01 Hz, 1H) 8.80 (d, J=1.88 Hz, 1H) 8.90 (s, 2H) 9.20 (s, 1H) 10.19(s, 1H).

Stage 67.15-Bromo-6-(pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

5-Bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.2,1 g, 2.53 mmol) and pyrrolidine (0.544 g, 5.06 mmol) were suspended iniPrOH (2.53 mL), and DIPEA (1.325 mL, 7.58 mmol) was added. The RM wassubjected to MW irradiation at 140° C. for 1 hr. The RM was treated with0.5 M HCl (40 mL) and extracted with EtOAc. The combined extracts weresequentially washed with 0.5 M HCl (40 mL) and brine, dried over Na₂SO₄and evaporated to dryness under reduced pressure. Crystallization from acyclohexane/EtOAc mixture yielded the title compound as an off-whitesolid. UPLC-MS (Condition 3) t_(R)=1.34 min, m/z=430.1/432.1 [M+H]⁺,m/z=428.3/430.3 [M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.76-2.01 (m,4H) 3.60-3.80 (m, 4H) 7.33 (d, J=8.20 Hz, 2H) 7.72-7.91 (m, 2H) 8.32 (d,J=1.95 Hz, 1H) 8.66 (d, J=1.95 Hz, 1H) 10.20 (s, 1H).

Example 685-(2-Aminopyrimidin-5-yl)-6-(pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 66 using5-bromo-6-(pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 67.1) and (2-aminopyrimidin-5-yl)boronic acid to afford a whitesolid. UPLC-MS (Condition 3) t_(R)=0.99 min, m/z=445.3 [M+H]⁺, m/z=443.1[M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.75-1.84 (m, 4H) 3.18-3.26 (m,4H) 6.77 (s, 2H) 7.34 (d, J=8.31 Hz, 2H) 7.86 (d, J=9.29 Hz, 2H) 7.95(d, J=2.45 Hz, 1H) 8.27 (s, 2H) 8.71 (d, J=2.45 Hz, 1H) 10.12 (s, 1H).

Example 696′-(Hydroxymethyl)-2-(pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 66 using5-bromo-6-(pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 67.1) and (6-(hydroxymethyl)pyridin-3-yl)boronic acid to afford awhite solid. UPLC-MS (Condition 3) t_(R)=1.0 min, m/z=459.2 [M+H]⁺,m/z=456.9 [M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.67-1.84 (m, 4H)3.05-3.21 (m, 4H) 4.62 (br. s, 2H) 5.50 (br. s, 1H) 7.34 (d, J=8.78 Hz,2H) 7.54 (d, J=8.03 Hz, 1H) 7.81 (dd, J=8.03, 2.26 Hz, 1H) 7.83-7.89 (m,2H) 8.01 (d, J=2.38 Hz, 1H) 8.51-8.55 (m, 1H) 8.76 (d, J=2.38 Hz, 1H)10.18 (s, 1H).

Example 702-((3S,4S)-3,4-Dihydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 75 using5-bromo-6-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 70.1) and pyridin-3-ylboronic acid to afford a white solid.UPLC-MS (condition 1) t_(R)=2.01 min, m/z=461.1 [M+H]⁺, m/z=459.2[M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 2.94 (d, J=11.74 Hz, 2H)3.37-3.45 (m, 2H) 3.85 (d, J=2.69 Hz, 2H) 5.04 (br. s, 2H) 7.35 (d,J=8.31 Hz, 2H) 7.51 (dd, J=7.09, 4.89 Hz, 1H) 7.81 (d, J=7.83 Hz, 1H)7.86 (d, 2H) 8.04 (d, J=2.45 Hz, 1H) 8.59 (dd, J=4.77, 1.59 Hz, 1H) 8.64(d, J=1.96 Hz, 1H) 8.76 (d, J=2.20 Hz, 1H) 10.18 (s, 1H).

Stage 70.15-Bromo-6-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

5-Bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 6.2,500 mg, 1.264 mmol, (3S,4S)-pyrrolidine-3,4-diol (157 mg, 1.517 mmol),DIPEA (442 μL, 2.53 mmol) and iPrOH (1.264 mL) were added to a MW vial,which was sealed and subjected to MW irradiation for 30 min at 140° C.The solvent was evaporated off under reduced pressure to give a residuewhich was treated with 0.5 M HCl (10 mL) and extracted with EtOAc. Thecombined extracts were washed with HCl 0.5 M and brine, diluted withMeOH (20 mL), dried over MgSO₄ and the solvent was evaporated off underreduced pressure and the product was crystallized from EtOAc/MeOHafforded the title compound as a white solid. UPLC-MS (condition 1)t_(R)=2.48 min, m/z=462.0/464.0 [M+H]⁺, m/z=460.0/462.0 [M−H]⁻; ¹H-NMR(400 MHz, DMSO-d₆) δ ppm 3.56 (d, J=11.25 Hz, 2H) 3.94-4.06 (m, 4H) 4.79(br. s, 2H) 7.34 (d, J=8.80 Hz, 2H) 7.88 (d, J=9.05 Hz, 2H) 8.38 (d,J=1.96 Hz, 1H) 8.71 (d, J=1.96 Hz, 1H) 10.34 (s, 1H).

Example 716-((3S,4R)-3,4-Dihydroxypyrrolidin-1-yl)-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

5-Bromo-6-((3S,4R)-3,4-dihydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 71.1, 60 mg, 0.13 mmol), pyrimidin-5-ylboronic acid (32.2 mg,0.26 mmol), Pd(PPh₃)₂Cl₂ (9.11 mg, 0.013 mmol) and Na₂CO₃ (55.0 mg,0.519 mmol) were added to a MW vial and treated with a mixture of DME(551 μL), water (157 μL) and EtOH (79 μL). The vial was sealed,evacuated/purged with argon and subjected to MW irradiation at 125° C.for 10 min. The RM was diluted with DME (3 mL), treated with Si-Thiol(Silicycle, 1.44 mmol/g, 54.1 mg, 0.078 mmol), centrifuged, thesupernatant was filtered and the solvent was evaporated off underreduced pressure to give a residue which was purified by preparative SFC(Column DEAP, isocratic 25% in 9 min.) to yield the title compound as awhite amorphous solid. UPLC-MS (Condition 3) t_(R)=0.83 min, m/z=462.1[M+H]⁺, m/z=460.1 [M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 3.05 (dd,J=10.76, 4.16 Hz, 2H) 3.26 (dd, J=10.51, 4.89 Hz, 2H) 3.98 (t, J=3.91Hz, 2H) 4.89 (br. s, 2H) 7.35 (d, J=8.56 Hz, 2H) 7.79-7.90 (m, 2H) 8.10(d, J=2.20 Hz, 1H) 8.79 (d, J=2.20 Hz, 1H) 8.88 (s, 2H) 9.20 (s, 1H)10.17 (s, 1H).

Stage 71.15-Bromo-6-((3S,4R)-3,4-dihydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

A mixture of 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 12.2, 1 g, 2.53 mmol) and (3R,4S)-pyrrolidine-3,4-diol (313 mg,3.03 mmol) in a mixture of DIPEA (0.883 mL, 5.06 mmol) and iPrOH (2.53mL) was subjected to MW irradiation at 140° C. for 30 min. The RM wastreated with 0.5 M aq. HCl (30 mL) and extracted with EtOAc. Thecombined extracts were washed with sat. NaHCO₃, brine and dried overNa₂SO₄. The crude product was purified by flash chromatography (RediSep®Silica gel column, 40 g, cyclohexane/EtOAc, from 50% to 100% EtOAc) toyield the title compound as a white amorphous solid. UPLC-MS (Condition3) t_(R)=0.98 min, m/z=462.1-464.0 [M+H]⁺, m/z=460.1-462.0 [M−H]⁻;¹H-NMR (400 MHz, DMSO-d₆) δ ppm 3.61 (dd, J=11.13, 4.28 Hz, 2H) 3.84(dd, J=10.76, 4.89 Hz, 2H) 4.10 (d, J=3.42 Hz, 2H) 4.96 (d, J=3.91 Hz,2H) 7.35 (d, J=8.80 Hz, 2H) 7.85 (d, J=8.80 Hz, 2H) 8.34 (s, 1H) 8.67(s, 1H) 10.21 (s, 1H).

Example 726-(trans-3-Hydroxy-4-methoxypyrrolidin-1-yl)-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 54 using5-bromo-6-(trans-3-hydroxy-4-methoxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 72.1) and pyrimidin-5-ylboronic acid to afford a white solid.UPLC-MS (condition 1) t_(R)=2.16 min, m/z=476.0 [M+H]⁺, m/z=474.0[M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 2.95 (d, J=11.25 Hz, 1H) 3.14(d, J=11.98 Hz, 1H) 3.23 (s, 3H) 3.28-3.35 (m, 1H) 3.46 (dd, J=11.98,4.40 Hz, 1H) 3.61-3.65 (m, 1H) 4.08 (br. s, 1H) 5.19 (d, J=3.67 Hz, 1H)7.36 (d, J=8.31 Hz, 2H) 7.85 (d, 2H) 8.12 (d, J=2.20 Hz, 1H) 8.79 (d,J=2.45 Hz, 1H) 8.89 (s, 2H) 9.21 (s, 1H) 10.19 (s, 1H).

Stage 72.15-Bromo-6-(trans-3-hydroxy-4-methoxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Stage 12.1 using5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.2)and Trans-4-methoxy-3-pyrrolidinol hydrochloride to afford a whiteamorphous solid. UPLC-MS (condition 1) t_(R)=2.65 min, m/z=475.9-477.9[M+H]⁺, m/z=474.0-475.9 [M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 3.31 (s,3H) 3.58 (d, J=11.49 Hz, 1H) 3.66 (d, J=12.23 Hz, 1H) 3.72-3.77 (m, 1H)3.92 (dd, J=11.86, 4.28 Hz, 1H) 3.97 (dd, J=12.10, 4.28 Hz, 1H) 4.22(br. s, 1H) 5.30 (d, J=3.18 Hz, 1H) 7.36 (d, J=8.31 Hz, 2H) 7.85 (d,J=9.29 Hz, 2H) 8.36 (d, J=2.20 Hz, 1H) 8.68 (d, J=2.20 Hz, 1H) 10.25 (s,1H).

Example 736-((3R,4R)-3-Hydroxy-4-methoxypyrrolidin-1-yl)-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

The title compound was obtained after chiral separation (preparativeHPLC, Chiralcel OD 20 μm 00CM-EK002, 50×5 cm, mobile phase:n-heptane/EtOH (85:15) (v/v), flow rate: 80 mL/min, Detection:UV 254 nm)of racemic6-((3S,4S)-3-hydroxy-4-methoxypyrrolidin-1-yl)-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Example 72, 128 mg, 0.269 mmol) to as an amorphous white solid. UPLC-MS(Condition 3) t_(R)=0.92 min, m/z=476.3 [M+H]⁺, m/z=474.4 [M−H]⁻; ¹H-NMR(400 MHz, DMSO-d₆) δ ppm 2.95 (d, J=11.49 Hz, 1H) 3.14 (d, J=11.98 Hz,1H) 3.23 (s, 3H) 3.28-3.31 (m, 1H) 3.46 (dd, J=11.98, 4.40 Hz, 1H)3.60-3.66 (m, 1H) 4.08 (br. s, 1H) 5.19 (d, J=3.67 Hz, 1H) 7.36 (d,J=8.31 Hz, 2H) 7.78-7.91 (m, 2H) 8.12 (d, J=2.45 Hz, 1H) 8.79 (d, J=2.45Hz, 1H) 8.89 (s, 2H) 9.21 (s, 1H) 10.19 (s, 1H).

Example 746-((3S,4S)-3-Hydroxy-4-methoxypyrrolidin-1-yl)-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

The title compound was obtained after chiral separation (preparativeHPLC, Chiralcel OD 20 μm 00CM-EK002, 50×5 cm, mobile phase:n-heptane/EtOH (85:15)formic acid, flow rate: 80 mL/min, Detection:UV254 nm) of racemic6-((3S,4S)-3-hydroxy-4-methoxypyrrolidin-1-yl)-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Example 72, 128 mg, 0.269 mmol) as white needles. UPLC-MS (Condition 3)t_(R)=0.92 min, m/z=476.3 [M+H]⁺, m/z=474.2 [M−H]⁻; ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 2.95 (d, J=11.49 Hz, 1H) 3.14 (d, J=11.98 Hz, 1H) 3.23(s, 3H) 3.30 (m, J=4.60 Hz, 1H) 3.46 (dd, J=12.10, 4.28 Hz, 1H) 3.63 (d,J=1.96 Hz, 1H) 4.08 (br. s, 1H) 5.19 (d, J=3.91 Hz, 1H) 7.36 (d, J=8.56Hz, 2H) 7.81-7.91 (m, 2H) 8.12 (d, J=2.20 Hz, 1H) 8.79 (d, J=2.20 Hz,1H) 8.89 (s, 2H) 9.21 (s, 1H) 10.19 (s, 1H).

Example 75(R)-6-(3-(Hydroxymethyl)pyrrolidin-1-yl)-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

(R)-5-Bromo-6-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 75.1, 60 mg, 0.13 mmol), pyrimidin-5-ylboronic acid (24.2 mg,0.196 mmol), Pd(PPh₃)₂Cl₂ (9.15 mg, 0.013 mmol) and Na₂CO₃ (41.5 mg,0.391 mmol) were added to a MW vial and treated with a mixture of DME(553 μL), water (158 μL) and EtOH (79 μL). The vial was sealed,evacuated/purged with argon and was subjected to MW irradiation at 80°C. for 2 h. The RM was diluted with THF (1 mL), treated with Si-Thiol(Silicycle, 1.27 mmol/g, 51.3 mg, 0.065 mmol), filtered and the filtratewas evaporated off under reduced pressure to give a residue which waspurified by preparative HPLC (Condition 12, 25% for 0.2 min then 25% to55% in 12 min) to yield the title compound as a white solid. UPLC-MS(condition 1) t_(R)=2.13 min, m/z=460.1-461.1 [M+H]⁺, m/z=458.2 [M−H]⁻;¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.53-1.64 (m, 1H) 1.81-1.90 (m, 1H)2.19-2.28 (m, 1H) 2.97 (dd, J=10.76, 6.85 Hz, 1H) 3.15-3.39 (m, 5H) 4.61(t, J=5.01 Hz, 1H) 7.35 (d, J=8.80 Hz, 2H) 7.85 (d, J=9.05 Hz, 2H) 8.09(d, J=2.20 Hz, 1H) 8.79 (d, J=2.20 Hz, 1H) 8.89 (s, 2H) 9.19 (s, 1H)10.17 (s, 1H).

Stage 75.1(R)-5-Bromo-6-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

5-Bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.2,500 mg, 1.264 mmol), (R)-beta-prolinol hydrochloride (191 mg, 1.39 mmol)and DIPEA (442 μL, 2.53 mmol) in iPrOH (1945 μL) were added to a MW vialand subjected to MW irradiation at 140° C. for 30 min. Additional(R)-beta-prolinol hydrochloride (34.8 mg, 0.253 mmol) and DIPEA (221 μL,1.264 mmol) were added to the mixture which was heated at 140° C. for afurther 30 min. The vial was cooled to RT and the RM was evaporated todryness under reduced pressure treated with 0.5 M HCl (20 mL) andextracted with EtOAc. The combined extracts were washed with 0.5 M HCl(10 mL), water, dried over MgSO₄ and evaporated to dryness under reducedpressure. Trituration in a cyclohexane/EtOAc mixture and filtration ofthe solid afforded the title compound as a white solid. UPLC-MS(condition 1) t_(R)=2.76 min, m/z=460.0-462.0 [M+H]⁺, m/z=458.0-460.0[M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.60-1.77 (m, 1H) 1.91-2.06 (m,1H) 2.28-2.42 (m, 1H) 3.35-3.51 (m, 2H) 3.56 (dd, J=11.00, 7.34 Hz, 1H)3.63-3.86 (m, 3H) 4.71 (br. s, 1H) 7.35 (d, J=8.56 Hz, 2H) 7.85 (d,J=9.05 Hz, 2H) 8.34 (d, J=1.96 Hz, 1H) 8.68 (d, J=1.96 Hz, 1H) 10.22 (s,1H).

Example 76(R)-2-(3-(Hydroxymethyl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 75 using(R)-5-bromo-6-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 75.1) and pyridin-3-ylboronic acid to afford a white solid.UPLC-MS (condition 1) t_(R)=1,89 min, m/z=459.1-460.1 [M+H]⁺,m/z=458.2-457.2 [M−H]−; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.50-1.61 (m,1H) 1.79-1.88 (m, 1H) 2.17-2.26 (m, 1H) 2.93-3.00 (m, 1H) 3.10-3.37 (m,5H) 4.60 (t, J=5.14 Hz, 1H) 7.34 (d, J=8.80 Hz, 2H) 7.48 (dd, J=7.82,4.89 Hz, 1H) 7.79-7.83 (m, 1H) 7.85 (d, J=9.05 Hz, 2H) 8.03 (d, J=2.20Hz, 1H) 8.57 (dd, J=4.89, 1.47 Hz, 1H) 8.64 (d, J=2.20 Hz, 1H) 8.76 (d,J=2.20 Hz, 1H) 10.17 (s, 1H).

Example 77(R)-2-(3-(hydroxymethyl)pyrrolidin-1-yl)-6′-methyl-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 75 using(R)-5-bromo-6-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 75.1) and (6-methylpyridin-3-yl)boronic acid to afford a whitesolid. UPLC-MS (condition 1) t_(R)=1.81 min, m/z=473.1-474.1 [M+H]⁺,m/z=472.2-471.2 [M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.52-1.61 (m,1H) 1.78-1.87 (m, 1H) 2.17-2.26 (m, 1H) 2.53 (s, 3H) 2.99 (dd, J=11.00,6.85 Hz, 1H) 3.11-3.20 (m, 2H) 3.21-3.29 (m, 2H) 3.33-3.37 (m, 1H) 4.60(t, J=5.14 Hz, 1H) 7.34 (dd, J=8.44, 3.06 Hz, 2H) 7.69 (dd, J=7.82, 2.20Hz, 1H) 7.85 (d, J=9.05 Hz, 2H) 7.98 (d, J=2.20 Hz, 1H) 8.49 (d, J=1.96Hz, 1H) 8.74 (d, J=2.20 Hz, 1H) 10.16 (s, 1H).

Example 78(S)-6-(3-(hydroxymethyl)pyrrolidin-1-yl)-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 75 using(S)-5-bromo-6-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 78.1) and pyrimidin-5-ylboronic acid to afford a white solid.UPLC-MS (condition 1) t_(R)=2.12 min, m/z=460.1-461.1 [M+H]⁺, m/z=458.2[M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.53-1.64 (m, 1H) 1.81-1.90 (m,1H) 2.20-2.28 (m, 1H) 2.97 (dd, J=10.76, 6.85 Hz, 1H) 3.15-3.40 (m, 5H)4.61 (t, J=5.14 Hz, 1H) 7.35 (d, J=8.80 Hz, 2H) 7.85 (d, J=9.05 Hz, 2H)8.09 (d, J=2.20 Hz, 1H) 8.79 (d, J=2.20 Hz, 1H) 8.89 (s, 2H) 9.19 (s,1H) 10.16 (s, 1H).

Stage 78.1(S)-5-bromo-6-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

5-Bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.2,500 mg, 1.264 mmol), (S)-beta-prolinol hydrochloride (226 mg, 1.643mmol), DIPEA (662 μL, 3.79 mmol) and iPrOH (1.945 mL) were added to a MWvial and subjected to MW irradiation at 140° C. for 60 min. The solventwas evaporated off under reduced pressure and the residue was treatedwith aq. 0.5 M HCl (20 mL) and extracted with EtOAc. The combinedextracts were washed with 0.5 M HCl (10 mL) and water, dried over MgSO₄and the solvent was evaporated off under reduced pressure to give theproduct which was triturated with cyclohexane, filtered and dried toafford the title compound as a white solid. UPLC-MS (condition 1)t_(R)=2.76 min, m/z=460.0/462.0 [M+H]⁺, m/z=458.0/460.0 [M−H]⁻; ¹H-NMR(400 MHz, DMSO-d₆) δ ppm 1.59-1.76 (m, 1H) 1.92-2.04 (m, 1H) 2.26-2.44(m, 1H) 3.37-3.50 (m, 2H) 3.56 (dd, J=11.00, 7.34 Hz, 1H) 3.67-3.85 (m,3H) 4.71 (br. s, 1H) 7.35 (d, J=8.56 Hz, 2H) 7.85 (d, 1H) 8.34 (d,J=1.96 Hz, 1H) 8.68 (d, J=1.96 Hz, 1H) 10.21 (s, 1H).

Example 79(S)-6-(3-(Hydroxymethyl)pyrrolidin-1-yl)-5-(2-methylpyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 75 using(S)-5-bromo-6-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 78.1) and2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine toafford an off-white solid. UPLC-MS (condition 1) t_(R)=2.37 min,m/z=474.1 [M+H]⁺, m/z=472.1 [M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm1.51-1.65 (m, 1H) 1.79-1.90 (m, 1H) 2.17-2.30 (m, 1H) 2.68 (s, 3H) 2.99(dd, J=10.76, 6.85 Hz, 1H) 3.11-3.23 (m, 2H) 3.22-3.30 (m, 3H) 4.61 (br.s, 1H) 7.35 (d, J=8.80 Hz, 2H) 7.85 (d, J=9.05 Hz, 2H) 8.04 (d, J=2.45Hz, 1H) 8.76 (s, 2H) 8.77 (d, J=2.44 Hz, 1H) 10.15 (s, 1H).

Example 80(S)-5-(2-Cyanopyrimidin-5-yl)-6-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 75 using(S)-5-bromo-6-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 78.1) and5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine-2-carbonitrileto afford a yellow solid. UPLC-MS (condition 1) t_(R)=2.54 min,m/z=485.0 [M+H]⁺, m/z=4831.1 [M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm1.55-1.67 (m, 1H) 1.82-1.93 (m, 1H) 2.21-2.30 (m, 1H) 2.98 (dd, J=11.00,7.09 Hz, 1H) 3.14-3.30 (m, 4H) 3.33-3.41 (m, 1H) 4.62 (t, J=5.26 Hz, 1H)7.36 (d, J=8.80 Hz, 2H) 7.85 (d, J=9.05 Hz, 2H) 8.17 (d, J=2.20 Hz, 1H)8.82 (d, J=2.20 Hz, 1H) 9.10 (s, 2H) 10.20 (s, 1H).

Example 81(S)-2-(3-(Hydroxymethyl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 75 using(S)-5-bromo-6-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 78.1) and pyridin-3-ylboronic acid to afford a white solid.UPLC-MS (condition 1) t_(R)=1.92 min, m/z=459.1-460.1 [M+H]⁺, m/z=457.2[M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.50-1.61 (m, 1H) 1.78-1.88 (m,1H) 2.17-2.25 (m, 1H) 2.96 (dd, J=11.00, 6.60 Hz, 1H) 3.10-3.37 (m, 5H)4.60 (t, J=5.14 Hz, 1H) 7.34 (d, J=8.56 Hz, 2H) 7.48 (dd, 1H) 7.81 (dt,J=7.82, 1.83 Hz, 1H) 7.85 (d, J=9.05 Hz, 2H) 8.03 (d, J=2.20 Hz, 1H)8.57 (dd, J=4.65, 1.47 Hz, 1H) 8.64 (d, J=1.96 Hz, 1H) 8.76 (d, J=2.45Hz, 1H) 10.17 (s, 1H).

Example 82(S)-2-(3-(Hydroxymethyl)pyrrolidin-1-yl)-6′-methyl-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 75 using(S)-5-bromo-6-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 78.1) and (6-methylpyridin-3-yl)boronic acid to afford a whitesolid. UPLC-MS (condition 1) t_(R)=1.80 min, m/z=473.1-474.1 [M+H]⁺,m/z=472.2-471.2 [M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.51-1.61 (m,1H) 1.78-1.88 (m, 1H) 2.17-2.25 (m, 1H) 2.53 (s, 3H) 2.99 (dd, J=11.00,6.85 Hz, 1H) 3.11-3.19 (m, 2H) 3.22-3.30 (m, 2H) 3.33-3.37 (m, 1H) 4.60(t, J=4.89 Hz, 1H) 7.34 (dd, J=8.31, 3.42 Hz, 3H) 7.69 (dd, J=7.95, 2.32Hz, 1H) 7.83-7.88 (m, 2H) 7.98 (d, J=2.45 Hz, 1H) 8.49 (d, J=2.20 Hz,1H) 8.74 (d, J=2.45 Hz, 1H) 10.16 (s, 1H).

Example 83(S)-6′-Ethyl-2-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 75 using(S)-5-bromo-6-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 78.1) and2-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine toafford a yellow solid. UPLC-MS (condition 1) t_(R)=1.90 min, m/z=487.0[M+H]⁺, m/z=485.1 [M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.27 (t,J=7.58 Hz, 3H) 1.50-1.62 (m, 1H) 1.77-1.89 (m, 1H) 2.15-2.28 (m, 1H)2.82 (q, J=7.58 Hz, 2H) 2.99 (dd, J=11.00, 6.60 Hz, 1H) 3.08-3.20 (m,2H) 3.21-3.30 (m, 2H) 3.29-3.38 (m, 1H) 4.60 (br. s, 1H) 7.34 (d, J=8.80Hz, 2H) 7.38 (d, J=8.07 Hz, 1H) 7.75 (dd, J=7.82, 1.96 Hz, 1H) 7.86 (d,J=9.05 Hz, 2H) 8.02 (d, J=2.20 Hz, 1H) 8.55 (d, J=1.96 Hz, 1H) 8.75 (d,J=2.20 Hz, 1H) 10.16 (s, 1H).

Example 84(S)-6′-(Fluoromethyl)-2-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

(S)-5-Bromo-6-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 78.1, 92 mg, 0.2 mmol) and2-(fluoromethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(prepared as described in US20090571601) (316 mg 30% ig, 0.4 mmol) weredissolved in DME (0.8 mL). A solution of 2 M NaHCO₃ (0.3 mL, 0.6 mmol)was added, the RM was flushed with argon, heated to 90° C. andPd(PPh₃)₂Cl₂ (14.0 mg, 0.02 mmol) was added. The RM was heated for 2 hat 90° C. After cooling at RT, the RM was dissolved in EtOAc and water,and extracted with EtOAc. The combined extracts were dried over Na₂SO₄and evaporated to dryness under reduced pressure. The crude product wasfirst purified by flash chromatography (RediSep® Silica gel column,DCM/MeOH from 2% to 5% MeOH), treated with Si-Thiol (100 mg) in MeOH andfurther purified by reverse phase chromatography (MPLC, Lichroprep 15-25μm column, water+0.1% formic acid/MeCN+0.1% formic acid, gradient 10% to38% MeCN+0.1% formic acid). The combined pure fractions were neutralizedwith NaHCO₃ and extracted with EtOAc. The combined organic phases weredried over Na₂SO₄ and evaporated to afford the title compound as anoff-white amorphous solid. HPLC (Condition 4) t_(R)=4.96 min, UPLC-MS(Condition 3) t_(R)=1.07 min, m/z=491.2 [M+H]⁺; ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 1.50-1.62 (m, 1H) 1.77-1.89 (m, 1H) 2.15-2.29 (m, 1H)2.92-3.02 (m, 1H) 3.07-3.38 (m, 4H) 3.42-3.53 (m, 2H) 4.60 (t, J=5.08Hz, 1H) 5.47 (s, 1H) 7.33 (d, J=8.99 Hz, 2H) 7.58 (d, J=7.82 Hz, 1H)7.77-7.92 (m, 3H) 8.02 (d, J=2.35 Hz, 1H) 8.64 (d, J=1.56 Hz, 1H) 8.75(d, J=2.74 Hz, 1H) 10.16 (s, 1H).

Example 85(S)-6′-Cyclopropyl-2-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 75 using(S)-5-bromo-6-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 78.1) and2-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine toafford an off-white solid. UPLC-MS (condition 1) t_(R)=2.30 min,m/z=499.0 [M+H]⁺, m/z=497.1 [M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm0.90-1.04 (m, 4H) 1.49-1.62 (m, 1H) 1.77-1.88 (m, 1H) 2.10-2.19 (m, 1H)2.18-2.26 (m, 1H) 2.99 (dd, J=11.00, 6.85 Hz, 1H) 3.09-3.20 (m, 2H)3.21-3.29 (m, 1H) 3.29-3.41 (m, 2H) 4.60 (br. s, 1H) 7.29-7.40 (m, 3H)7.64 (dd, J=8.07, 2.20 Hz, 1H) 7.85 (d, J=9.05 Hz, 2H) 7.99 (d, J=2.20Hz, 1H) 8.45 (d, J=2.20 Hz, 1H) 8.73 (d, J=2.20 Hz, 1H) 10.14 (s, 1H).

Example 86(S)-5′-Fluoro-2-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

(S)-5-Bromo-6-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 78.1, 60 mg, 0.13 mmol), (5-fluoropyridin-3-yl)boronic acid (60.8mg, 0.261 mmol), Pd(PPh₃)₂Cl₂ (9.15 mg, 0.013 mmol) and Na₂CO₃ (41.5 mg,0.391 mmol) were added to a MW vial. The vial was sealed,evacuated/purged with argon, and DME (553 μL), water (158 μL) and EtOH(79 μL) were added. The RM was subjected to MW irradiation at 120° C.for 15 min. The RM was diluted with DME (2 mL), treated with Si-Thiol(Silicycle, 1.27 mmol/g, 103 mg, 0.130 mmol), filtered and the filtratewas evaporated off under reduced pressure to give a residue which waspurified by preparative HPLC (Condition 12, 15% to 45% in 14 min) toyield the title compound as a yellow solid. UPLC-MS (condition 1)t_(R)=1.90 min, m/z=487.0 [M+H]⁺, m/z=485.1 [M−H]⁻; ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 1.27 (t, J=7.58 Hz, 3H) 1.50-1.62 (m, 1H) 1.77-1.89 (m,1H) 2.15-2.28 (m, 1H) 2.82 (q, J=7.58 Hz, 2H) 2.99 (dd, J=11.00, 6.60Hz, 1H) 3.08-3.20 (m, 2H) 3.21-3.30 (m, 2H) 3.29-3.38 (m, 1H) 4.60 (br.s, 1H) 7.34 (d, J=8.80 Hz, 2H) 7.38 (d, J=8.07 Hz, 1H) 7.75 (dd, J=7.82,1.96 Hz, 1H) 7.86 (d, J=9.05 Hz, 2H) 8.02 (d, J=2.20 Hz, 1H) 8.55 (d,J=1.96 Hz, 1H) 8.75 (d, J=2.20 Hz, 1H) 10.16 (s, 1H).

Example 87(S)-5′-Fluoro-2-(3-(hydroxymethyl)pyrrolidin-1-yl)-6′-methyl-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 52 using(S)-6′-chloro-5′-fluoro-2-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide(Example 89) to afford an off-white solid. HPLC (Condition 4) t_(R)=5.2min, UPLC-MS (Condition 7) m/z=491.2 [M+H]⁺; ¹H-NMR (400 MHz, DMSO-d₆) δppm 1.56 (m, J=12.10, 7.40 Hz, 1H) 1.74-1.91 (m, 1H) 2.10-2.28 (m, 1H)2.48 (s, 3H) 2.98 (dd, J=11.14, 6.84 Hz, 1H) 3.09-3.19 (m, 2H) 3.21-3.38(m, 3H) 4.60 (t, J=5.28 Hz, 1H) 7.33 (d, J=9.38 Hz, 2H) 7.71 (d, J=10.17Hz, 1H) 7.79-7.89 (m, 2H) 8.01 (d, J=1.00 Hz, 1H) 8.34 (s, 1H) 8.74 (d,J=2.30 Hz, 1H) 10.14 (s, 1H).

Example 88(S)-6′-Chloro-2-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 86 using(S)-5-bromo-6-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 78.1) and (6-chloropyridin-3-yl)boronic acid and to afford anoff-white solid. UPLC-MS (condition 1) t_(R)=2.51 min, m/z=493.0-495.0[M+H]⁺, m/z=494.1-493.1 [M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm1.51-1.65 (m, 1H) 1.78-1.92 (m, 1H) 2.23 (ddd, J=13.63, 7.09, 6.91 Hz,1H) 2.98 (dd, J=10.88, 6.97 Hz, 1H) 3.12-3.22 (m, 2H) 3.21-3.31 (m, 3H,in HDO) 4.62 (br. s, 1H) 7.35 (d, J=8.80 Hz, 2H) 7.61 (d, J=8.31 Hz, 1H)7.85 (d, J=9.29 Hz, 2H) 7.89 (dd, J=8.31, 2.45 Hz, 1H) 8.03 (d, J=2.44Hz, 1H) 8.49 (d, J=2.45 Hz, 1H) 8.77 (d, J=2.45 Hz, 1H) 10.17 (s, 1H).

Example 89(S)-6′-Chloro-5′-fluoro-2-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 53 using(S)-5-bromo-6-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 78.1) and2-chloro-3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridineto afford an off-white solid. HPLC (Condition 4) t_(R)=5.69 min, UPLC-MS(Condition 7) m/z=511.1 [M+H]⁺; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm1.48-1.65 (m, 1H) 1.84 (m, J=5.90 Hz, 1H) 2.15-2.28 (m, 1H) 2.98 (dd,J=10.95, 7.04 Hz, 1H) 3.11-3.41 (m, 5H) 4.61 (t, J=5.28 Hz, 1H) 7.34 (d,J=9.38 Hz, 2H) 7.83 (d, J=9.38 Hz, 2H) 7.99-8.09 (m, 2H) 8.35 (d, J=1.00Hz, 1H) 8.76 (d, J=2.35 Hz, 1H) 10.16 (s, 1H).

Example 90(S)-5′-Cyano-2-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 75 using(S)-5-bromo-6-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 78.1) and5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile to affordan off-white solid. UPLC-MS (condition 1) t_(R)=2.38 min, m/z=484.0[M+H]⁺, m/z=482.0 [M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.47-1.67 (m,1H) 1.78-1.91 (m, 1H) 2.16-2.30 (m, 1H) 2.96 (dd, J=11.00, 6.85 Hz, 1H)3.12-3.19 (m, 2H) 3.19-3.26 (m, 1H) 3.25-3.31 (m, 1H) 3.33-3.39 (m, 1H)4.62 (t, J=5.26 Hz, 1H) 7.35 (d, J=8.56 Hz, 2H) 7.85 (d, J=9.29 Hz, 2H)8.08 (d, J=2.45 Hz, 1H) 8.40 (t, J=2.08 Hz, 1H) 8.79 (d, J=2.20 Hz, 1H)8.91 (d, J=2.20 Hz, 1H) 9.02 (d, J=1.96 Hz, 1H) 10.17 (s, 1H).

Example 91(S)-6′-Cyano-2-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 86 using(S)-5-bromo-6-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 78.1) and (6-cyanopyridin-3-yl)boronic acid to afford a lightgreen solid. UPLC-MS (condition 1) t_(R)=2.46 min, m/z=484.1 [M+H]⁺,m/z=482.1 [M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.47-1.65 (m, 1H)1.78-1.93 (m, 1H) 2.17-2.29 (m, 1H) 2.96 (dd, J=10.64, 6.97 Hz, 1H)3.11-3.23 (m, 2H) 3.24-3.40 (m, 3H in HDO) 4.62 (br. s, 1H) 7.35 (d,J=8.31 Hz, 2H) 7.85 (d, J=8.56 Hz, 2H) 8.02-8.17 (m, 3H) 8.79 (d, J=1.22Hz, 1H) 8.84 (s, 1H) 10.19 (s, 1H).

Example 925′-Fluoro-2-(trans-3-hydroxy-4-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 86 usingbromo-6-(trans-3-hydroxy-4-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 92.1) and (5-fluoropyridin-3-yl)boronic acid to afford a whitesolid. UPLC-MS (Condition 3) t_(R)=0.93 min, m/z=493.2 [M+H], m/z=491.4[M−H]⁺, m/z=537.4 [M+formic acid−H]; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm1.99-2.18 (m, 1H) 2.83-2.96 (m, 1H) 3.07-3.18 (m, 1H) 3.18-3.32 (m, 2H)3.41-3.50 (m, 2H) 3.93-4.03 (m, 1H) 4.62-4.71 (m, 1H) 4.99 (d, J=4.27Hz, 1H) 7.36 (d, J=9.03 Hz, 2H) 7.82-7.93 (m, 3H) 8.08 (d, J=2.38 Hz,1H) 8.52 (d, J=1.63 Hz, 1H) 8.61 (d, J=2.63 Hz, 1H) 8.78 (d, J=2.38 Hz,1H) 10.20 (s, 1H).

Stage 92.15-Bromo-6-(trans-3-hydroxy-4-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Stage 12.1 using5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Example 35)and 4-(hydroxymethyl)pyrrolidin-3-ol hydrochloride to afford anoff-white solid. UPLC-MS (Condition 3) t_(R)=0.98 min, m/z=476.2/478.2[M+H]⁺, m/z=474.0/476.0 [M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm2.11-2.23 (m, 1H) 3.25-3.34 (m, 2H) 3.39-3.49 (m, 1H) 3.50-3.62 (m, 2H)3.83-3.96 (m, 2H) 4.04-4.12 (m, 1H) 4.70 (t, J=5.27 Hz, 1H) 5.07 (d,J=4.37 Hz, 1H) 7.33 (d, J=8.75 Hz, 2H) 7.83 (d, J=9.00 Hz, 2H) 8.32 (d,J=2.06 Hz, 1H) 8.66 (d, J=1.80 Hz, 1H) 10.21 (s, 1H).

Example 93(R)-6-(3-Aminopyrrolidin-1-yl)-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

A mixture of (R)-tert-butyl(1-(3-bromo-5-((4-(trifluoromethoxy)phenyl)carbamoyl)pyridin-2-yl)pyrrolidin-3-yl)carbamate(Stage 93.1, 60 mg, 0.110 mmol), pyrimidin-5-ylboronic acid (21 mg,0.164 mmol), 2M Na₂CO₃ (0.2 mL, 0.4 mmol) and DME (4 mL) was flushedwith argon. PdCl₂(dppf)(CH₂Cl₂) (10 mg, 0.012 mmol) was added and themixture was subjected to MW irradiation 140° C. for 30 min. The RM wasfiltered through a PL-Thiol MP SPE cartridge (StratoSpheres™, 6 mL), thecartridge was washed with MeOH and the solvent was evaporated off underreduced pressure to give a residue which was purified by preparativeLC-MS to afford the title compound. LC-MS (Condition 6) t_(R)=0.88 min,m/z=445.0 [M+H]⁺.

Stage 93.1 (R)-tert-Butyl(1-(3-bromo-5-((4-(trifluoromethoxy)phenyl)carbamoyl)pyridin-2-yl)pyrrolidin-3-yl)carbamate

A mixture of 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 12.2, 0.5 g, 1.264 mmol), (R)-tert-butyl pyrrolidin-3-ylcarbamate(283 mg, 1.517 mmol), iPrOH (4 mL) and DIPEA (0.442 mL, 0.327 g, 2.53mmol) were subjected to MW irradiation at 140° C. for 30 min. The vialwas cooled to RT and the RM was added to water (100 mL) and theresulting precipitate was collected by filtration. The obtained solidwas washed with water (50 mL) and dried to afford the title compound asan off-white powder. LC-MS (Condition 6) t_(R)=1.47 min, m/z=488.9/490.9[M+H—H2C═C(CH3)2], m/z=545/547.0 [M+H]⁺.

Example 94(R)-2-(3-Aminopyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 93 using (R)-tert-butyl(1-(3-bromo-5-((4-(trifluoromethoxy)phenyl)carbamoyl)pyridin-2-yl)pyrrolidin-3-yl)carbamate(Stage 93.1) and pyridin-3-ylboronic acid. LC-MS (Condition 6)t_(R)=0.79 min, m/z=444.0 [M+H]⁺.

Example 95(R)-2-(3-Aminopyrrolidin-1-yl)-6′-methyl-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 93 using (R)-tert-butyl(1-(3-bromo-5-((4-(trifluoromethoxy)phenyl)carbamoyl)pyridin-2-yl)pyrrolidin-3-yl)carbamate(Stage 93.1) and (6-methylpyridin-3-yl)boronic acid. LC-MS (Condition 6)t_(R)=0.79 min, m/z=458.0 [M+H]⁺.

Example 96(S)-6-(3-Aminopyrrolidin-1-yl)-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 93 using (S)-tert-butyl(1-(3-bromo-5-((4-(trifluoromethoxy)phenyl)carbamoyl)pyridin-2-yl)pyrrolidin-3-yl)carbamate(Stage 96.1) and pyrimidin-5-ylboronic acid. LC-MS (Condition 6)t_(R)=0.89 min, m/z=445.0 [M+H]⁺.

Stage 96.1 (S)-tert-Butyl(1-(3-bromo-5-((4-(trifluoromethoxy)phenyl)carbamoyl)pyridin-2-yl)pyrrolidin-3-yl)carbamate

The title compound was prepared in an analogous fashion to thatdescribed in Stage 93.1 using5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.2)and (S)-tert-butyl pyrrolidin-3-ylcarbamate. LC-MS (Condition 6)t_(R)=1.46 min, m/z=488.9 [M+H—H2C═C(CH3)2], m/z=544.9 [M+H]⁺.

Example 97(S)-2-(3-Aminopyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 93 using (S)-tert-butyl(1-(3-bromo-5-((4-(trifluoromethoxy)phenyl)carbamoyl)pyridin-2-yl)pyrrolidin-3-yl)carbamate(Stage 96.1) and pyridin-3-ylboronic acid. LC-MS (Condition 6) t_(R)=0.8min, m/z=444.0 [M+H]⁺.

Example 98(S)-2-(3-Aminopyrrolidin-1-yl)-6′-methyl-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 93 using (S)-tert-butyl(1-(3-bromo-5-((4-(trifluoromethoxy)phenyl)carbamoyl)pyridin-2-yl)pyrrolidin-3-yl)carbamate(Stage 96.1) and (6-methylpyridin-3-yl)boronic acid. LC-MS (Condition 6)t_(R)=0.79 min, m/z=448.0 [M+H]⁺.

Example 99(R)-6-(3-(Methylamino)pyrrolidin-1-yl)-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 93 using (R)-tert-butyl(1-(3-bromo-5-((4-(trifluoromethoxy)phenyl)carbamoyl)pyridin-2-yl)pyrrolidin-3-yl)(methyl)carbamate(Stage 99.1) and pyrimidin-5-ylboronic acid. LC-MS (Condition 6)t_(R)=0.89 min, m/z=459.0 [M+H]⁺.

Stage 99.1 (R)-tert-Butyl(1-(3-bromo-5-((4-(trifluoromethoxy)phenyl)carbamoyl)pyridin-2-yl)pyrrolidin-3-yl)(methyl)carbamate

The title compound was prepared in an analogous fashion to that in Stage93.1 using 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 12.2) and (R)-tert-butyl methyl(pyrrolidin-3-yl)carbamate. LC-MS(Condition 6) t_(R)=1.59 min, m/z=559.0/561.0 [M+H]⁺, m/z=502.9/504.9[M+H—H2C═C(CH3)2].

Example 100(R)-2-(3-(Methylamino)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 93 using (R)-tert-butyl(1-(3-bromo-5-((4-(trifluoromethoxy)phenyl)carbamoyl)pyridin-2-yl)pyrrolidin-3-yl)(methyl)carbamate(Stage 99.1) and pyridin-3-ylboronic acid. LC-MS (Condition 6) t_(R)=0.8min, m/z=458.0 [M+H]⁺.

Example 101(R)-6′-Methyl-2-(3-(methylamino)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 93 using (R)-tert-butyl(1-(3-bromo-5-((4-(trifluoromethoxy)phenyl)carbamoyl)pyridin-2-yl)pyrrolidin-3-yl)(methyl)carbamate(Stage 99.1) and (6-methylpyridin-3-yl)boronic acid. LC-MS (Condition 6)t_(R)=0.81 min, m/z=472.0 [M+H]⁺.

Example 102(S)-6-(3-(Methylamino)pyrrolidin-1-yl)-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 93 using (5)-tert-butyl(1-(3-bromo-5-((4-(trifluoromethoxy)phenyl)carbamoyl)pyridin-2-yl)pyrrolidin-3-yl)(methyl)carbamate(Stage 102.1) and pyrimidin-5-ylboronic acid. LC-MS (Condition 6)t_(R)=0.89 min, m/z=459.0 [M+H]⁺.

Stage 102.1 (5)-tert-Butyl(1-(3-bromo-5-((4-(trifluoromethoxy)phenyl)carbamoyl)pyridin-2-yl)pyrrolidin-3-yl)(methyl)carbamate

The title compound was prepared in an analogous fashion to thatdescribed in Stage 93.1 using5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.2)and (S)-tert-butyl methyl(pyrrolidin-3-yl)carbamate. LC-MS (Condition 6)t_(R)=1.59 min, m/z=558.8/560.8 [M+H]⁺, m/z=502.9/504.9[M+H—H2C═C(CH3)2].

Example 103(S)-2-(3-(Methylamino)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 93 using (S)-tert-butyl(1-(3-bromo-5-((4-(trifluoromethoxy)phenyl)carbamoyl)pyridin-2-yl)pyrrolidin-3-yl)(methyl)carbamate(Stage 102.1) and pyridin-3-ylboronic acid. LC-MS (Condition 6)t_(R)=0.8 min, m/z=458.0 [M+H]⁺.

Example 104(S)-6′-Methyl-2-(3-(methylamino)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 93 using (S)-tert-butyl(1-(3-bromo-5-((4-(trifluoromethoxy)phenyl)carbamoyl)pyridin-2-yl)pyrrolidin-3-yl)(methyl)carbamate(Stage 102.1) and (6-methylpyridin-3-yl)boronic acid. LC-MS (Condition6) t_(R)=0.8 min, m/z=472.0 [M+H]⁺.

Example 105(R)-6-(3-(Aminomethyl)pyrrolidin-1-yl)-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 93 using (R)-tert-butyl((1-(3-bromo-5-((4-(trifluoromethoxy)phenyl)carbamoyl)pyridin-2-yl)pyrrolidin-3-yl)methyl)carbamate(Stage 105.1) and pyrimidin-5-ylboronic acid. LC-MS (Condition 6)t_(R)=0.86 min, m/z=459.0 [M+H]⁺.

Stage 105.1 (R)-tert-Butyl((1-(3-bromo-5-((4-(trifluoromethoxy)phenyl)carbamoyl)pyridin-2-yl)pyrrolidin-3-yl)methyl)carbamate

The title compound was prepared in an analogous fashion to thatdescribed in Stage 93.1 using5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.2)and (S)-tert-butyl (pyrrolidin-3-ylmethyl)carbamate. LC-MS (Condition 6)t_(R)=2.7 min, m/z=559.0/561.0 [M+H]⁺, m/z=581.0 [M+Na]⁺.

Example 106(R)-2-(3-(Aminomethyl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 93 using (R)-tert-butyl((1-(3-bromo-5-((4-(trifluoromethoxy)phenyl)carbamoyl)pyridin-2-yl)pyrrolidin-3-yl)methyl)carbamate(Stage 105.1) and pyridin-3-ylboronic acid. LC-MS (Condition 6)t_(R)=0.8 min, m/z=458.0 [M+H]⁺.

Example 107(R)-2-(3-(Aminomethyl)pyrrolidin-1-yl)-6′-methyl-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 93 using (R)-tert-butyl((1-(3-bromo-5-((4-(trifluoromethoxy)phenyl)carbamoyl)pyridin-2-yl)pyrrolidin-3-yl)methyl)carbamate(Stage 105.1) and (6-methylpyridin-3-yl)boronic acid. LC-MS (Condition6) t_(R)=0.81 min, m/z=472.0 [M+H]⁺.

Example 108(S)-6-(3-(Aminomethyl)pyrrolidin-1-yl)-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 93 using (S)-tert-butyl((1-(3-bromo-5-((4-(trifluoromethoxy)phenyl)carbamoyl)pyridin-2-yl)pyrrolidin-3-yl)methyl)carbamate(Stage 108.1) and pyrimidin-5-ylboronic acid. LC-MS (Condition 6)t_(R)=0.87 min, m/z=459.0 [M+H]⁺.

Stage 108.1 (S)-tert-Butyl((1-(3-bromo-5-((4-(trifluoromethoxy)phenyl)carbamoyl)pyridin-2-yl)pyrrolidin-3-yl)methyl)carbamate

The title compound was prepared in an analogous fashion to thatdescribed in Stage 93.1 using5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.2)and (R)-tert-butyl (pyrrolidin-3-ylmethyl)carbamate. LC-MS (Condition 6)t_(R)=1.46 min, m/z=558.9 [M+H]⁺, m/z=581.0 [M+Na]⁺.

Example 109(S)-2-(3-(Aminomethyl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 93 using (S)-tert-butyl((1-(3-bromo-5-((4-(trifluoromethoxy)phenyl)carbamoyl)pyridin-2-yl)pyrrolidin-3-yl)methyl)carbamate(Stage 108.1) and pyridin-3-ylboronic acid. LC-MS (Condition 6)t_(R)=0.8 min, m/z=458.0 [M+H]⁺.

Example 110(S)-2-(3-(Aminomethyl)pyrrolidin-1-yl)-6′-methyl-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 93 using (S)-tert-butyl((1-(3-bromo-5-((4-(trifluoromethoxy)phenyl)carbamoyl)pyridin-2-yl)pyrrolidin-3-yl)methyl)carbamate(Stage 108.1) and (6-methylpyridin-3-yl)boronic acid. LC-MS (Condition6) t_(R)=0.79 min, m/z=472.0 [M+H]⁺.

Example 111(S)-2-(3-(Aminomethyl)pyrrolidin-1-yl)-6′-methoxy-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 93 using (S)-tert-butyl((1-(3-bromo-5-((4-(trifluoromethoxy)phenyl)carbamoyl)pyridin-2-yl)pyrrolidin-3-yl)methyl)carbamate(Stage 108.1) and (6-methoxypyridin-3-yl)boronic acid. LC-MS (Condition6) t_(R)=0.92 min, m/z=488.0 [M+H]⁺.

Example 1126-(3-(Dimethylamino)pyrrolidin-1-yl)-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 36 using5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.2)and pyrimidin-5-ylboronic acid to afford a white solid. UPLC-MS(condition 1) t_(R)=1.59 min, m/z=473.1 [M+H]⁺, m/z=471.1 [M−H]⁻; ¹H-NMR(400 MHz, DMSO-d₆) δ ppm 1.95-2.11 (m, 1H) 2.17-2.31 (m, 1H) 2.73-2.86(m, 6H) 2.98-3.10 (m, 1H) 3.09-3.19 (m, 1H) 3.58 (d, J=6.6 Hz, 1H)3.70-3.77 (m, 1H) 3.80-3.89 (m, 1H) 7.37 (d, J=8.6 Hz, 2H) 7.85 (d,J=4.9 Hz, 2H) 8.19 (d, J=2.4 Hz, 1H) 8.82 (d, J=2.4 Hz, 1H) 8.93 (s, 2H)9.23 (s, 1H) 9.83 (br. s, 1H)(NH+) 10.26 (s, 1H).

Example 1136-(3-(2-Hydroxypropan-2-yl)pyrrolidin-1-yl)-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

5-Bromo-6-(3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 113.1, 98 mg, 0.2 mmol) and pyrimidin-5-ylboronic acid (49.6 mg,0.4 mmol) were dissolved in DME (0.8 mL) and EtOH (0.12 mL). A solutionof 2 M NaHCO₃ (0.3 mL, 0.6 mmol) was added, the RM was flushed withargon, then Pd(PPh₃)₂Cl₂ (14.0 mg, 0.02 mmol) was added. The RM wasstirred under argon at 95° C. for 2 h in a sealed pressure safe tube.After cooling at RT, the RM was dissolved in EtOAc, washed with brine,dried over Na₂SO₄ and evaporated to dryness under reduced pressure. Thecrude product was purified by flash chromatography (RediSep® Silica gelcolumn, DCM/MeOH from 2% to 5% MeOH) and treated with Si-Thiol (80 mg)in MeOH to afford the title compound as a white solid. HPLC (Condition4) t_(R)=4.94 min, UPLC-MS (Condition 3) t_(R)=1.01 min, m/z=532.3[M+H]⁺; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 0.90-1.08 (m, 6H) 1.58-1.83 (m,2H) 1.99-2.15 (m, 1H) 3.05-3.23 (m, 3H) 3.25-3.35 (m, 1H) 4.29 (s, 1H)7.33 (d, J=8.60 Hz, 2H) 7.75-7.87 (m, 2H) 8.07 (d, J=2.35 Hz, 1H) 8.77(d, J=2.35 Hz, 1H) 8.87 (s, 2H) 9.17 (s, 1H) 10.14 (s, 1H).

Stage 113.15-Bromo-6-(3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Stage 33.1 using5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.2)and 3-(1-hydroxy-1-methyl-ethyl)-pyrrolidine (US2010160280) and wasobtained as an off-white solid. HPLC (Condition 4) t_(R)=6.11 min,UPLC-MS (Condition 7) m/z=490.1 [M+H]⁺.

Example 1142-(3-(2-Hydroxypropan-2-yl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 113 using5-bromo-6-(3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 113.1) and pyridin-3-ylboronic acid to afford a white solid. HPLC(Condition 4) t_(R)=4.68 min, UPLC-MS (Condition 7) m/z=487.2 [M+H]⁺;¹H-NMR (400 MHz, DMSO-d₆) δ ppm 0.87-1.10 (m, 6H) 1.53-1.80 (m, 2H)1.96-2.12 (m, 1H) 3.00-3.20 (m, 3H) 3.24-3.33 (m, 1H) 4.25 (s, 1H) 7.32(d, J=8.99 Hz, 2H) 7.46 (dd, J=7.82, 5.08 Hz, 1H) 7.74-7.89 (m, 3H) 8.00(d, J=2.35 Hz, 1H) 8.55 (dd, J=4.69, 1.56 Hz, 1H) 8.61 (d, J=1.56 Hz,1H) 8.74 (d, J=2.35 Hz, 1H) 10.14 (s, 1H).

Example 1152-(3-(2-Hydroxypropan-2-yl)pyrrolidin-1-yl)-6′-methyl-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 113 using5-bromo-6-(3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 113.1) and (6-methylpyridin-3-yl)boronic acid to afford anoff-white amorphous solid. HPLC (Condition 4) t_(R)=4.38 min, UPLC-MS(Condition 7) m/z=501.2 [M+H]⁺; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.00 (d,J=16.03 Hz, 6H) 1.55-1.80 (m, 2H) 1.95-2.12 (m, 1H) 2.48 (s, 3H)2.99-3.20 (m, 3H) 3.22-3.35 (m, 1H) 4.26 (s, 1H) 7.32 (dd, J=8.21, 5.86Hz, 3H) 7.67 (dd, J=7.82, 2.35 Hz, 1H) 7.78-7.89 (m, 2H) 7.96 (d, J=2.35Hz, 1H) 8.47 (d, J=2.35 Hz, 1H) 8.72 (d, J=2.35 Hz, 1H) 10.13 (s, 1H).

Example 1165-(Pyrimidin-5-yl)-6-(2-oxa-6-azaspiro[3.4]octan-6-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 86 using5-bromo-6-(2-oxa-6-azaspiro[3.4]octan-6-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 116.1) and pyrimidin-5-ylboronic acid to afford a white solid.UPLC-MS (condition 1) t_(R)=2.35 min, m/z=472.0 [M+H]⁺, m/z=470.0[M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 2.00-2.15 (m, 2H) 3.11 (t,J=6.72 Hz, 2H) 3.44 (s, 2H) 4.41-4.45 (m, 2H) 4.45-4.50 (m, 2H) 7.36 (d,J=8.31 Hz, 2H) 7.85 (d, J=9.05 Hz, 2H) 8.11 (d, J=2.45 Hz, 1H) 8.79 (d,J=2.45 Hz, 1H) 8.90 (s, 2H) 9.20 (s, 1H) 10.19 (s, 1H).

Stage 116.15-Bromo-6-(2-oxa-6-azaspiro[3.4]octan-6-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Stage 12.1 using5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Example 35)and 2-oxa-6-azaspiro[3,4]octane to afford white needles. UPLC-MS(condition 1) t_(R)=2.93 min, m/z=471.9/473.9 [M+H]⁺, m/z=469.9/471.9[M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 2.20 (t, J=6.85 Hz, 2H) 3.73 (t,J=6.97 Hz, 2H) 3.95 (s, 2H) 4.51 (d, J=5.87 Hz, 2H) 4.60 (d, J=5.87 Hz,2H) 7.35 (d, J=8.31 Hz, 2H) 7.82-7.88 (m, 2H) 8.36 (d, J=2.20 Hz, 1H)8.69 (d, J=1.96 Hz, 1H) 10.24 (s, 1H).

Example 1174-(2-Oxooxazolidin-3-yl)-3-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)benzamide

4-Bromo-3-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)benzamide(Stage 117.1, 100 mg, 0.228 mmol), oxazolidin-2-one (79 mg, 0.913 mmol),copper iodide (4.35 mg, 0.023 mmol) and finely ground K₃PO₄ (143 mg,0.672 mmol) were added to a MW vial. The vial was sealed,evacuated/purged with argon and a solution oftrans-N,N′-dimethylcyclohexane-1,2-diamine (7.20 μL, 0.046 mmol) indioxane (456 μL) was added. The RM was then stirred at 110° C. for 20hr. The RM was diluted with EtOAc (5 mL), washed with 1M HCl (20 mL) andextracted with EtOAc. The combined extracts were sequentially washedwith NH₄OH (32%)/NH₄Cl (sat.) 1:5 (10 mL), and brine (10 mL), dried overNa₂SO₄, and the mixture was evaporated to dryness under reducedpressure. The crude product was purified by flash chromatography(RediSep® Silica gel column, 12 g, cyclohexane/EtOAc-EtOH+0.1% NH4OH(9:1), from 20% to 90% EtOAc-EtOH+0.1% NH4OH (9:1)). Second purificationwas performed by preparative HPLC (Condition 13, from 5% to 100% in 14min) afforded the title compound as a brown solid. UPLC-MS (condition 1)t_(R)=2.13 min, m/z=445.1 [M+H]⁺, m/z=443.2 [M−H]⁻; ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 4.03-4.21 (m, 2H) 4.32-4.49 (m, 2H) 7.39 (d, J=8.31 Hz,2H) 7.72-7.83 (m, 1H) 7.84-7.93 (m, 2H) 8.06-8.17 (m, 2H) 8.96 (s, 2H)9.22 (s, 1H) 10.49 (s, 1H).

Stage 117.14-Bromo-3-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)-benzamide

4-Bromo-3-iodo-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 117.2, 3g, 6.17 mmol), pyrimidin-5-ylboronic acid (841 mg, 6.79 mmol),Pd(PPh₃)₂Cl₂ (217 mg, 0.309 mmol) and Na₂CO₃ (1.963 g, 18.52 mmol) in amixture of DME (17.28 mL), water (4.94 mL), EtOH (2.469 mL) was degassedand stirred at 80° C. for 23 h under argon. Additionalpyrimidin-5-ylboronic acid (76 mg, 0.613 mmol) was added to the RM andstirring was continued for 5 h. The RM was treated with Si-Thiol(Silicycle, 1.27 mmol/g, 1.215 g, 1.543 mmol), filtered and the filtratewas evaporated off under reduced pressure to give a residue which waspurified by flash chromatography (Silica gel column, 80 g,cyclohexane/EtOAc, from 10% to 45% EtOAc) to yield the title compound asa white crystalline solid. UPLC-MS (condition 1) t_(R)=2.80 min,m/z=437.9-439.9 [M+H]⁺, m/z=436.0-438.0 [M−H]⁻.

Stage 117.2 4-Bromo-3-iodo-N-(4-(trifluoromethoxy)phenyl)-benzamide

The title compound was prepared in an analogous fashion to thatdescribed in Stage 1.2 using 4-bromo-3-iodobenzoic acid and4-(trifluoromethoxy)aniline to afford a white solid. UPLC-MS(condition 1) t_(R)=3.64 min, m/z=485.7 [M+H]⁺, m/z=483.8 [M−H]⁻; Brpattern. ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 7.38 (d, J=8.3 Hz, 2H)7.82-7.93 (m, 4H) 8.47 (d, J=1.7 Hz, 1H) 10.52 (s, 1H).

Example 1186-(3-Hydroxypiperidin-1-yl)-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

5-Bromo-6-(3-hydroxypiperidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 118.1, 60 mg, 0.130 mmol), pyrimidin-5-ylboronic acid (24.2 mg,0.196 mmol), Pd₂(dba)₃ (2.388 mg, 2.61 μmol),2-dichlohexylphosphino-2′-4′-6′-triisoprophylbiphenyl (XPhos, 4.97 mg,10.43 μmol) and K₃PO₄ (83 mg, 0.391 mmol) were added to a MW vial. Thevial was sealed, evacuated/purged with argon, and BuOH was added. The RMwas stirred at 100° C. for 16 h. The RM was diluted with THF (1 mL),treated with Si-Thiol (Silicycle, 1.44 mmol/g, 45.3 mg, 0.065 mmol),filtered and the filtrate was evaporated off under reduced pressure togive a residue which was purified by preparative HPLC (Condition 12, 25%for 0.2 min then 25% to 55% in 12 min) to yield the title compound as awhite solid. UPLC-MS (condition 1) t_(R)=2.31 min, m/z=460.1-461.1[M+H]⁺, m/z=458.2-459.2 [M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm1.21-1.39 (m, 2H) 1.56-1.65 (m, 1H) 1.77-1.86 (m, 1H) 2.63 (dd, J=11.86,8.44 Hz, 1H) 2.75-2.84 (m, 1H) 3.25-3.38 (m, 1H) 3.43-3.55 (m, 2H) 4.74(d, J=3.91 Hz, 1H) 7.37 (d, J=8.80 Hz, 2H) 7.86 (d, J=9.05 Hz, 2H) 8.19(d, J=2.20 Hz, 1H) 8.80 (d, J=2.20 Hz, 1H) 9.08 (s, 2H) 9.21 (s, 1H)10.30 (s, 1H).

Stage 118.15-Bromo-6-(3-hydroxypiperidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

5-Bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Example 35,1 g, 2.53 mmol), 3-hydroxypiperidine (307 mg, 3.03 mmol) and DIPEA (883μL, 5.06 mmol) in iPrOH (2528 μL) were added to a MW vial and subjectedto MW irradiation at 140° C. for 60 min. The vial was cooled to RT andthe RM was evaporated to dryness under reduced pressure, treated with0.5 M HCl (25 mL) and extracted with EtOAc. The combined extracts werewashed with HCl 0.5 M, brine, dried over MgSO₄ and evaporated to drynessunder reduced pressure. The crude product was purified by flashchromatography (Silica gel column, 24 g, cyclohexane/EtOAc-EtOH+0.1%NH₄OH (9:1)), from 15% to 60% EtOAc-EtOH+0.1% NH₄OH (9:1)) to afford thetitle compound as a white foam. UPLC-MS (condition 1) t_(R)=2.89 min,m/z=460.0-462.0 [M+H]⁺, m/z=458.0-460.0 [M−H]⁻; ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 1.27-1.45 (m, 1H) 1.46-1.66 (m, 1H) 1.73-1.87 (m, 1H)1.89-2.01 (m, 1H) 2.74 (dd, J=12.23, 9.29 Hz, 1H) 2.92 (t, J=10.64 Hz,1H) 3.56-3.70 (m, 1H) 3.70-3.81 (m, 1H) 3.91 (dd, J=12.10, 3.30 Hz, 1H)4.87 (d, J=4.40 Hz, 1H) 7.36 (d, J=8.56 Hz, 2H) 7.85 (d, J=9.05 Hz, 2H)8.42 (d, J=1.96 Hz, 1H) 8.76 (d, J=1.96 Hz, 1H) 10.37 (s, 1H).

Example 1192-(3-Hydroxypiperidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 118 using5-bromo-6-(3-hydroxypiperidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 118.1) and pyridin-3-ylboronic acid to afford a white solid.UPLC-MS (condition 1) t_(R)=2.06 min, m/z=459.1-460.1 [M+H]⁺,m/z=457.2-458.2 [M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.20-1.38 (m,2H) 1.53-1.61 (m, 1H) 1.79-1.86 (m, 1H) 2.59 (dd, J=12.23, 9.05 Hz, 1H)2.69-2.78 (m, 1H) 3.35-3.41 (m, 1H) 3.43-3.50 (m, 1H) 3.56-3.62 (m, 1H)4.73 (d, J=4.40 Hz, 1H) 7.37 (d, J=8.80 Hz, 2H) 7.50-7.54 (m, 1H) 7.86(d, J=9.05 Hz, 2H) 8.02 (dt, J=8.01, 1.86 Hz, 1H) 8.11 (d, J=2.45 Hz,1H) 8.57-8.61 (m, 1H) 8.77 (d, J=2.20 Hz, 1H) 8.81 (d, J=1.71 Hz, 1H)10.30 (s, 1H).

Example 1202-(3-Hydroxypiperidin-1-yl)-6′-methyl-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 118 using5-bromo-6-(3-hydroxypiperidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 118.1) and (6-methylpyridin-3-yl)boronic acid to afford a whitesolid. UPLC-MS (condition 1) t_(R)=1.88 min, m/z=473.1-474.1 [M+H]⁺,m/z=471.1-472.1 [M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.19-1.38 (m,2H) 1.53-1.61 (m, 1H) 1.79-1.86 (m, 1H) 2.53 (s, 3H) 2.57 (dd, J=12.10,9.17 Hz, 1H) 2.72 (t, J=10.51 Hz, 1H) 3.35-3.41 (m, 1H) 3.42-3.51 (m,1H) 3.56-3.63 (m, 1H) 4.73 (d, J=4.40 Hz, 1H) 7.34-7.39 (m, 3H) 7.86 (d,J=8.80 Hz, 2H) 7.90 (dd, J=8.07, 2.20 Hz, 1H) 8.06 (d, J=2.20 Hz, 1H)8.67 (d, J=1.96 Hz, 1H) 8.74 (d, J=2.20 Hz, 1H) 10.29 (s, 1H).

Example 121(R)-6-(3-Hydroxypiperidin-1-yl)-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 118 using(R)-5-bromo-6-(3-hydroxypiperidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 121.1) and pyrimidin-5-ylboronic acid to afford a white solid.UPLC-MS (condition 1) t_(R)=2.21 min, m/z=460.01 [M+H]⁺, m/z=458.2[M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.21-1.39 (m, 2H) 1.56-1.65 (m,1H) 1.77-1.86 (m, 1H) 2.63 (dd, J=11.86, 8.44 Hz, 1H) 2.75-2.84 (m, 1H)3.35-3.38 (m, 1H) 3.43-3.49 (m, 1H) 3.49-3.55 (m, 1H) 4.74 (s, 1H) 7.37(d, J=8.56 Hz, 2H) 7.83-7.89 (m, 2H) 8.19 (d, J=2.45 Hz, 1H) 8.80 (d,J=2.45 Hz, 2H) 9.08 (s, 1H) 9.21 (s, 1H) 10.30 (s, 1H).

Stage 121.1(R)-5-Bromo-6-(3-hydroxypiperidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Stage 12.1 using5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Example 35)and (R)-(+)-3-hydroxypiperidine hydrochloride to afford a brown oil.UPLC-MS (condition 1) t_(R)=3.38 min, m/z=460.0-462.0 [M+H]⁺,m/z=458.0-461.0 [M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.28-1.41 (m,1H) 1.49-1.63 (m, 1H) 1.75-1.85 (m, 1H) 1.90-1.98 (m, 1H) 2.73 (dd,J=12.23, 9.29 Hz, 1H) 2.87-2.96 (m, 1H) 3.56-3.69 (m, 1H) 3.75 (d,J=12.72 Hz, 1H) 3.91 (dd, J=12.10, 3.55 Hz, 1H) 4.88 (s, 1H) 7.36 (d,J=8.80 Hz, 2H) 7.82-7.89 (m, 2H) 8.42 (d, J=2.20 Hz, 1H) 8.76 (d, J=2.20Hz, 1H) 10.37 (s, 1H).

Example 122(R)-2-(3-Hydroxypiperidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 118 using(R)-5-bromo-6-(3-hydroxypiperidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 121.1) and pyridin-3-ylboronic acid to afford a white solid.UPLC-MS (condition 1) t_(R)=1.98 min, m/z=459.1 [M+H]⁺, m/z=457.2[M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.18-1.38 (m, 2H) 1.52-1.61 (m,1H) 1.76-1.87 (m, 1H) 2.58 (dd, J=12.23, 9.05 Hz, 1H) 2.68-2.78 (m, 1H)3.34-3.41 (m, 1H) 3.41-3.51 (m, 1H) 3.54-3.62 (m, 1H) 4.72 (d, J=3.67Hz, 1H) 7.36 (d, J=8.80 Hz, 2H) 7.51 (dd, J=7.95, 4.77 Hz, 1H) 7.83-7.89(m, 2H) 7.99-8.04 (m, 1H) 8.10 (d, J=2.20 Hz, 1H) 8.58 (d, J=4.65 Hz,1H) 8.76 (d, J=2.20 Hz, 1H) 8.79-8.83 (m, 1H) 10.29 (s, 1H).

Example 123(R)-2-(3-Hydroxypiperidin-1-yl)-6′-methyl-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 118 using(R)-5-bromo-6-(3-hydroxypiperidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 121.1) and (6-methylpyridin-3-yl)boronic acid to afford a whitesolid. UPLC-MS (condition 1) t_(R)=2.28 min, m/z=473.1 [M+H]⁺, m/z=471.2[M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.18-1.39 (m, 2H) 1.53-1.62 (m,1H) 1.77-1.86 (m, 1H) 2.54 (s, 3H) 2.55-2.62 (m, 1H) 2.68-2.77 (m, 1H)3.42-3.51 (m, 2H) 3.55-3.63 (m, 1H) 4.72 (s, 1H) 7.36 (d, J=9.05 Hz, 2H)7.40 (d, J=8.07 Hz, 1H) 7.83-7.88 (m, 2H) 7.92-7.98 (m, 1H) 8.07 (d,J=1.96 Hz, 1H) 8.67-8.72 (m, 1H) 8.75 (d, J=2.20 Hz, 1H) 10.29 (s, 1H).

Example 124(S)-6-(3-Hydroxypiperidin-1-yl)-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 118 using(S)-5-bromo-6-(3-hydroxypiperidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 124.1) and pyrimidin-5-ylboronic acid to afford a white solid.UPLC-MS (condition 1) t_(R)=2.22 min, m/z=460.0 [M+H]⁺, m/z=458.1[M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.21-1.39 (m, 2H) 1.56-1.65 (m,1H) 1.77-1.86 (m, 1H) 2.63 (dd, J=11.86, 8.19 Hz, 1H) 2.75-2.84 (m, 1H)3.35-3.39 (m, 1H) 3.43-3.49 (m, 1H) 3.49-3.55 (m, 1H) 4.74 (s, 1H) 7.37(d, J=8.31 Hz, 2H) 7.83-7.89 (m, 2H) 8.19 (d, J=2.20 Hz, 1H) 8.80 (d,J=2.20 Hz, 1H) 9.08 (s, 2H) 9.21 (s, 1H) 10.30 (s, 1H).

Stage 124.1(S)-5-Bromo-6-(3-hydroxypiperidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Stage 12.1 using5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Example 35)and (S)-3-hydroxypiperidine hydrochloride to afford a brown oil. UPLC-MS(condition 1) t_(R)=3.36 min, m/z=460.0-462.0, m/z=458.0-460.1; ¹H-NMR(400 MHz, DMSO-d₆) δ ppm 1.28-1.41 (m, 1H) 1.49-1.63 (m, 1H) 1.75-1.84(m, 1H) 1.90-1.97 (m, 1H) 2.73 (dd, J=12.10, 9.17 Hz, 1H) 2.87-2.96 (m,1H) 3.59-3.68 (m, 1H) 3.75 (d, J=12.72 Hz, 1H) 3.87-3.95 (m, 1H) 4.88(s, 1H) 7.36 (d, J=8.80 Hz, 2H) 7.82-7.88 (m, 2H) 8.42 (d, J=1.96 Hz,1H) 8.76 (d, J=1.96 Hz, 1H) 10.37 (s, 1H).

Example 125(S)-2-(3-Hydroxypiperidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 118 using(S)-5-bromo-6-(3-hydroxypiperidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 124.1) and pyridin-3-ylboronic acid to afford a white solid.UPLC-MS (condition 1) t_(R)=1.97 min, m/z=459.1 [M+H]⁺, m/z=457.1[M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.19-1.37 (m, 2H) 1.53-1.61 (m,1H) 1.82 (d, J=8.56 Hz, 1H) 2.58 (dd, J=12.23, 9.05 Hz, 1H) 2.69-2.78(m, 1H) 3.34-3.40 (m, 1H) 3.41-3.51 (m, 1H) 3.55-3.62 (m, 1H) 4.73 (d,J=4.40 Hz, 1H) 7.36 (d, J=8.56 Hz, 2H) 7.52 (dd, J=7.95, 4.77 Hz, 1H)7.83-7.89 (m, 2H) 8.02 (dt, J=7.82, 1.83 Hz, 1H) 8.10 (d, J=2.20 Hz, 1H)8.59 (dd, J=4.65, 1.22 Hz, 1H) 8.76 (d, J=2.20 Hz, 1H) 8.81 (d, J=1.71Hz, 1H) 10.29 (s, 1H).

Example 126(S)-2-(3-Hydroxypiperidin-1-yl)-6′-methyl-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 118 using(S)-5-bromo-6-(3-hydroxypiperidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 124.1) and (6-methylpyridin-3-yl)boronic acid to afford a whitesolid. UPLC-MS (condition 1) t_(R)=2.16 min, m/z=473.1 [M+H]⁺, m/z=471.1[M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.19-1.39 (m, 2H) 1.53-1.62 (m,1H) 1.78-1.86 (m, 1H) 2.55 (s, 3H) 2.55-2.62 (m, 1H) 2.69-2.78 (m, 1H)3.42-3.51 (m, 2H) 3.55-3.63 (m, 1H) 4.37-5.01 (m, 1H) 7.36 (d, J=8.56Hz, 2H) 7.42 (d, J=8.07 Hz, 1H) 7.83-7.89 (m, 2H) 7.93-8.00 (m, 1H) 8.07(d, J=2.20 Hz, 1H) 8.71 (d, J=1.22 Hz, 1H) 8.75 (d, J=2.20 Hz, 1H) 10.29(s, 1H).

Example 1272-(3-Hydroxyazetidin-1-yl)-6′-methyl-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 57 using5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.2)and (6-methylpyridin-3-yl)boronic acid to afford an off-white solid.HPLC (Condition 4) t_(R)=4.1 min, UPLC-MS (Condition 3) t_(R)=0.92 min,m/z=445.2 [M+H]⁺; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 2.52 (s, 3H) 3.45 (dd,J=9.38, 4.30 Hz, 2H) 3.85 (dd, J=9.38, 6.65 Hz, 2H) 4.34 (m, J=4.70 Hz,1H) 5.51 (d, J=5.08 Hz, 1H) 7.34 (t, J=8.02 Hz, 3H) 7.72 (dd, J=7.82,2.35 Hz, 1H) 7.79-7.88 (m, 2H) 7.94-8.01 (m, 1H) 8.49 (d, J=2.35 Hz, 1H)8.69-8.77 (m, 1H) 10.19 (s, 1H).

Example 1286-(3-Hydroxy-3-methylazetidin-1-yl)-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

5-Bromo-6-(3-hydroxy-3-methylazetidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 128.1, 89 mg, 0.2 mmol) and pyrimidin-5-ylboronic acid (50 mg,0.4 mmol) were dissolved in DME (0.8 mL). A solution of 2 M Na₂CO₃(0.300 mL, 0.6 mmol) and EtOH (120 μL) were added, the mixture wasflushed with argon, Pd(PPh₃)₂Cl₂ (17 mg, 0.02 mmol) was added and the RMwas heated at 95° C. for 3 h in a pressure safe vial. After cooling atRT, the RM was treated with EtOAc and washed with brine. The organicphase was dried over Na₂SO₄ and evaporated to dryness under reducedpressure. The crude product was purified by flash chromatography(RediSep® Silica gel column, first EtOAc/MeOH from 0 to 10% MeOH; thensecond flash DCM/MeOH, from 2% to 5% MeOH) and treated with Si-Thiol (80mg) in MeOH to afford the title compound as a white crystalline solid.HPLC (Condition 4) t_(R)=4.74 min, UPLC-MS (Condition 7) m/z=446.3[M+H]⁺; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.29 (s, 4H) 3.50-3.64 (m, 3H)5.49 (s, 1H) 7.34 (d, J=8.60 Hz, 2H) 7.83 (d, J=8.99 Hz, 2H) 8.09 (d,J=1.56 Hz, 1H) 8.78 (d, J=1.95 Hz, 1H) 8.90 (s, 2H) 9.20 (s, 1H) 10.20(s, 1H).

Stage 128.15-Bromo-6-(3-hydroxy-3-methylazetidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

5-Bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.2,1.38 g, 3.5 mmol) and 3-methyl-azetidin-3-ol (HCl salt, 519 mg, 4.2mmol) were dissolved in iPrOH (3.5 mL). DIPEA (1.4 mL, 8 mmol) was addedand the RM mixture was heated at 140° C. for 4 h in a pressure safevial. After cooling at RT, the RM was dissolved in EtOAc, washed with0.5 M. HCl and brine. The organic phase was dried over Na₂SO₄ and themixture was evaporated to dryness under reduced pressure. The crudeproduct was purified by flash chromatography (RediSep® Silica gelcolumn, n-hexane/EtOAc, from 50 to 100% EtOAc) to afford the titlecompound as a white crystalline solid. HPLC (Condition 4) t_(R)=5.59min, UPLC-MS (Condition 3) t_(R)=0.92 min, m/z=448.1 [M+H]⁺.

Example 1296-(3-Hydroxy-3-methylazetidin-1-yl)-5-(2-methylpyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 128 using5-bromo-6-(3-hydroxy-3-methylazetidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 128.1) and2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine toafford an off-white solid. HPLC (Condition 4) t_(R)=4.75 min, UPLC-MS(Condition 3) t_(R)=0.95 min, m/z=460.2 [M+H]⁺; ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 1.29 (s, 3H) 2.68 (s, 3H) 3.58 (s, 4H) 5.47 (s, 1H)7.26-7.40 (m, 2H) 7.77-7.92 (m, 2H) 8.04 (d, J=2.35 Hz, 1H) 8.67-8.82(m, 3H) 10.19 (s, 1H).

Example 1302-(3-Hydroxy-3-methylazetidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 128 using5-bromo-6-(3-hydroxy-3-methylazetidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 128.1) and pyridin-3-ylboronic acid. HPLC (Condition 4)t_(R)=4.45 min, UPLC-MS (Condition 3) t_(R)=0.95 min, m/z=445.3 [M+H]⁺;¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.27 (s, 3H) 3.46-3.61 (m, 4H) 5.43 (s,1H) 7.33 (d, J=8.99 Hz, 2H) 7.44-7.54 (m, 1H) 7.74-7.90 (m, 3H) 8.02 (d,J=1.95 Hz, 1H) 8.58 (dd, J=4.69, 1.56 Hz, 1H) 8.64 (d, J=2.35 Hz, 1H)8.75 (d, J=2.35 Hz, 1H) 10.19 (s, 1H).

Example 1312-(3-Hydroxy-3-methylazetidin-1-yl)-6′-methyl-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 128 using5-bromo-6-(3-hydroxy-3-methylazetidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 128.1) and (6-methylpyridin-3-yl)boronic acid. HPLC (Condition 4)t_(R)=4.22 min, UPLC-MS (Condition 3) t_(R)=0.95 min, m/z=459.3 [M+H]⁺;¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.27 (s, 3H) 2.52 (s, 3H) 3.45-3.61 (m,4H) 5.41 (s, 1H) 7.34 (dd, J=8.21, 5.47 Hz, 3H) 7.72 (dd, J=8.21, 2.35Hz, 1H) 7.80-7.88 (m, 2H) 7.97 (d, J=2.35 Hz, 1H) 8.49 (d, J=1.96 Hz,1H) 8.73 (d, J=2.35 Hz, 1H) 10.18 (s, 1H).

Example 1325′-Fluoro-2-(3-hydroxy-3-methylazetidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 128 using5-bromo-6-(3-hydroxy-3-methylazetidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 128.1) and (5-fluoropyridin-3-yl)boronic acid. HPLC (Condition 4)t_(R)=5.15 min, UPLC-MS (Condition 3) t_(R)=1.04 min, m/z=463.1 [M+H]⁺;¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.29 (s, 3H) 3.57 (m, J=2.70 Hz, 4H)5.48 (s, 1H) 7.34 (d, J=8.99 Hz, 2H) 7.84 (d, J=8.99 Hz, 3H) 8.01-8.10(m, 1H) 8.53 (s, 1H) 8.61 (d, J=2.74 Hz, 1H) 8.72-8.84 (m, 1H) 10.20 (s,1H).

Example 1335′-Fluoro-2-(3-hydroxy-3-methylazetidin-1-yl)-6′-methyl-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 52 using6′-chloro-5′-fluoro-2-(3-hydroxy-3-methylazetidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide(Example 134) and trimethyl-boroxine. HPLC (Condition 4) t_(R)=5.26 min,UPLC-MS (Condition 3) t_(R)=1.09 min, m/z=477.3 [M+H]⁺; ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 1.29 (s, 3H) 2.42-2.55 (m, 3H) 3.50-3.65 (m, 4H) 5.46 (d,J=0.78 Hz, 1H) 7.34 (d, J=8.99 Hz, 2H) 7.74 (d, J=10.56 Hz, 1H) 7.83 (d,J=8.60 Hz, 2H) 7.97-8.05 (m, 1H) 8.37 (s, 1H) 8.71-8.78 (m, 1H) 10.19(s, 1H).

Example 1346′-Chloro-5′-fluoro-2-(3-hydroxy-3-methylazetidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 53 using5-bromo-6-(3-hydroxy-3-methylazetidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 128.1) and2-chloro-3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine.HPLC (Condition 4) t_(R)=5.74 min, UPLC-MS (Condition 3) t_(R)=1.16 min,m/z=497.2 [M+H]⁺; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.30 (s, 3H) 3.60 (s,4H) 5.48 (s, 1H) 7.34 (d, J=8.99 Hz, 2H) 7.83 (d, J=8.99 Hz, 2H)8.00-8.15 (m, 2H) 8.38 (d, J=1.95 Hz, 1H) 8.77 (d, J=2.35 Hz, 1H) 10.21(s, 1H).

Example 1356-(3-(Hydroxymethyl)azetidin-1-yl)-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 128 using5-bromo-6-(3-(hydroxymethyl)azetidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 135.1) and pyrimidin-5-ylboronic acid. HPLC (Condition 4)t_(R)=4.6 min, UPLC-MS (Condition 3) t_(R)=0.90 min, m/z=446.3 [M+H]⁺;¹H-NMR (400 MHz, DMSO-d₆) δ ppm 2.53-2.68 (m, 1H) 3.38-3.53 (m, 4H)3.63-3.77 (m, 2H) 4.68 (t, J=1.00 Hz, 1H) 7.33 (d, J=8.99 Hz, 2H) 7.83(d, J=8.99 Hz, 2H) 8.05 (d, J=1.96 Hz, 1H) 8.77 (d, J=1.00 Hz, 1H) 8.89(s, 2H) 9.15-9.31 (m, 1H) 10.18 (s, 1H).

Stage 135.15-Bromo-6-(3-(hydroxymethyl)azetidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Stage 128.1 using5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.2)and azetidin-3-yl-methanol. HPLC (Condition 4) t_(R)=5.33 min, UPLC-MS(Condition 3) t_(R)=1.06 min, m/z=446.2.

Example 1366-(3-(Hydroxymethyl)azetidin-1-yl)-5-(2-methylpyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 128 using5-bromo-6-(3-(hydroxymethyl)azetidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 135.1) and2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine. HPLC(Condition 4) t_(R)=4.61 min, UPLC-MS (Condition 3) t_(R)=0.95 min,m/z=460.3 [M+H]⁺; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 2.55-2.63 (m, 1H) 2.67(s, 3H) 3.39-3.52 (m, 4H) 3.73 (t, J=8.60 Hz, 2H) 4.69 (t, J=5.28 Hz,1H) 7.34 (d, J=8.99 Hz, 2H) 7.79-7.88 (m, 2H) 8.01 (d, J=2.35 Hz, 1H)8.70-8.82 (m, 3H) 10.18 (s, 1H).

Example 1372-(3-(Hydroxymethyl)azetidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 128 using5-bromo-6-(3-(hydroxymethyl)azetidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 135.1) and pyridin-3-ylboronic acid. HPLC (Condition 4)t_(R)=4.38 min, UPLC-MS (Condition 3) t_(R)=0.92 min, m/z=445.2 [M+H]⁺;¹H-NMR (400 MHz, DMSO-d₆) δ ppm 2.53-2.68 (m, 1H) 3.37-3.49 (m, 4H) 3.68(t, J=8.41 Hz, 2H) 4.66 (t, J=5.28 Hz, 1H) 7.33 (d, J=8.99 Hz, 2H) 7.49(dd, J=7.82, 4.69 Hz, 1H) 7.84 (d, J=8.99 Hz, 3H) 7.99 (d, J=2.35 Hz,1H) 8.54-8.60 (m, 1H) 8.64 (d, J=1.96 Hz, 1H) 8.72-8.78 (m, 1H) 10.18(s, 1H).

Example 1382-(3-(Hydroxymethyl)azetidin-1-yl)-6′-methyl-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 128 using5-bromo-6-(3-(hydroxymethyl)azetidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 135.1) and (6-methylpyridin-3-yl)boronic acid. HPLC (Condition 4)t_(R)=4.18 min, UPLC-MS (Condition 3) t_(R)=0.93 min, m/z=459.2 [M+H]⁺;¹H-NMR (400 MHz, DMSO-d₆) δ ppm 2.48 (s, 3H) 2.58 (t, J=5.87 Hz, 1H)3.39-3.47 (m, 4H) 3.69 (t, J=8.60 Hz, 2H) 4.66 (t, J=5.28 Hz, 1H) 7.33(m, J=8.40, 2.50 Hz, 3H) 7.71 (dd, J=7.82, 2.35 Hz, 1H) 7.81-7.86 (m,2H) 7.95 (d, J=2.35 Hz, 1H) 8.49 (d, J=2.35 Hz, 1H) 8.73 (d, J=1.95 Hz,1H) 10.17 (s, 1H).

Example 1395′-Fluoro-2-(3-(hydroxymethyl)azetidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 128 using5-bromo-6-(3-(hydroxymethyl)azetidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 135.1) and3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine. HPLC(Condition 4) t_(R)=5.02 min, UPLC-MS (Condition 3) t_(R)=1.01 min,m/z=463.2 [M+H]⁺; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 2.56-2.68 (m, 1H)3.37-3.52 (m, 4H) 3.71 (t, J=8.60 Hz, 2H) 4.68 (t, J=1.00 Hz, 1H) 7.34(d, J=8.60 Hz, 2H) 7.77-7.90 (m, 3H) 8.04 (d, J=2.35 Hz, 1H) 8.49-8.55(m, 1H) 8.60 (d, J=2.74 Hz, 1H) 8.76 (d, J=2.35 Hz, 1H) 10.18 (s, 1H).

Example 1405′-Fluoro-2-(3-(hydroxymethyl)azetidin-1-yl)-6′-methyl-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 52 using6′-chloro-5′-fluoro-2-(3-(hydroxymethyl)azetidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide(Example 141). HPLC (Condition 4) t_(R)=5.15 min, UPLC-MS (Condition 3)t_(R)=1.05 min, m/z=477.2 [M+H]⁺; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm2.45-2.53 (m, 3H) 2.55-2.70 (m, 1H) 3.36-3.52 (m, 4H) 3.72 (t, J=8.41Hz, 2H) 4.68 (t, J=5.08 Hz, 1H) 7.33 (d, J=8.99 Hz, 2H) 7.74 (d, J=10.56Hz, 1H) 7.79-7.89 (m, 2H) 7.97-8.02 (m, 1H) 8.37 (d, J=1.56 Hz, 1H) 8.74(m, J=2.00, 1.20 Hz, 1H) 10.18 (s, 1H).

Example 1416′-Chloro-5′-fluoro-2-(3-(hydroxymethyl)azetidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 53 using5-bromo-6-(3-(hydroxymethyl)azetidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 135.1) and2-chloro-3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine.HPLC (Condition 4) t_(R)=5.57 min, UPLC-MS (Condition 3) t_(R)=1.13 min,m/z=497.1 [M+H]⁺; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 2.55-2.70 (m, 1H)3.39-3.53 (m, 4H) 3.73 (t, J=1.00 Hz, 2H) 4.69 (t, J=1.00 Hz, 1H) 7.34(d, J=8.21 Hz, 2H) 7.83 (m, J=9.40 Hz, 2H) 8.04 (d, J=1.95 Hz, 1H) 8.09(m, J=9.40 Hz, 1H) 8.38 (d, J=1.95 Hz, 1H) 8.77 (d, J=2.35 Hz, 1H) 10.19(s, 1H).

Example 1426-(3-(2-Hydroxypropan-2-yl)azetidin-1-yl)-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 128 using5-bromo-6-(3-(2-hydroxypropan-2-yl)azetidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 142.1) and pyrimidin-5-ylboronic acid to afford an off-whitepowder. HPLC (Condition 4) t_(R)=4.88 min, UPLC-MS (Condition 7)m/z=474.2 [M+H]⁺; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 0.94 (s, 6H) 2.50-2.58(m, 1H) 3.63 (d, J=7.43 Hz, 4H) 4.39 (s, 1H) 7.34 (d, J=8.99 Hz, 2H)7.49-7.68 (m, 1H) 7.79-7.91 (m, 2H) 8.06 (dd, J=2.15, 0.98 Hz, 1H)8.73-8.81 (m, 1H) 8.85-8.96 (m, 1H) 9.20 (d, J=0.78 Hz, 1H) 10.19 (s,1H).

Stage 142.15-Bromo-6-(3-(2-hydroxypropan-2-yl)azetidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Stage 128.1 using5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.2)and 2-azetidin-3-yl-propan-2-ol (WO2010138589) to afford an off-whitecrystalline product. HPLC (Condition 4) t_(R)=5.84 min, UPLC-MS(Condition 7) m/z=474.1 [M+H]⁺.

Example 1432-(3-(2-Hydroxypropan-2-yl)azetidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 128 using5-bromo-6-(3-(2-hydroxypropan-2-yl)azetidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 142.1) and pyridin-3-ylboronic acid to afford an off-whitepowder. HPLC (Condition 4) t_(R)=4.61 min, UPLC-MS (Condition 7)m/z=473.1 [M+H]⁺; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 0.93 (s, 6H) 3.24-3.34(m, 1H) 3.59 (m, J=8.60 Hz, 4H) 4.36 (s, 1H) 7.33 (d, J=8.60 Hz, 2H)7.49 (dd, J=7.82, 4.69 Hz, 1H) 7.84 (d, J=8.99 Hz, 3H) 8.00 (d, J=1.95Hz, 1H) 8.53-8.62 (m, 1H) 8.65 (d, J=1.95 Hz, 1H) 8.74 (d, J=1.96 Hz,1H) 10.18 (s, 1H).

Example 1442-(3-(2-Hydroxypropan-2-yl)azetidin-1-yl)-6′-methyl-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 128 using5-bromo-6-(3-(2-hydroxypropan-2-yl)azetidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 142.1) and (6-methylpyridin-3-yl)boronic acid to afford anoff-white foam. HPLC (Condition 4) t_(R)=4.37 min, UPLC-MS (Condition 7)m/z=487.2 [M+H]⁺; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 0.93 (s, 6H) 2.49 (s,3H) 3.31 (br. s, 1H) 3.54-3.66 (m, 4H) 4.36 (d, J=0.78 Hz, 1H) 7.22-7.43(m, 3H) 7.73 (dd, J=7.82, 2.35 Hz, 1H) 7.79-7.88 (m, 2H) 7.95 (d, J=2.35Hz, 1H) 8.51 (d, J=1.96 Hz, 1H) 8.72 (d, J=2.35 Hz, 1H) 10.17 (s, 1H).

Example 1452-(1,4-Diazepan-1-yl)-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

A mixture of5-bromo-6-(1,4-diazepan-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 145.1, 51 mg, 0.111 mmol), pyridin-3-ylboronic acid (13.6 mg,0.111 mmol), and Na₂CO₃ (35 mg, 0.333 mmol) in a mixture of DME (2.4mL), EtOH (0.32 mL) and water (0.48 mL) was flushed with argon.Pd(PPh₃)₂Cl₂ (4 mg, 0.005 mmol) was added and the mixture was subjectedto MW irradiation at 125° C. for 20 min. The vial was cooled to RT andthe RM was evaporated to dryness under reduced pressure to give aresidue that was triturated with THF and filtered. The filtrate wasevaporated to dryness under reduced pressure and the crude product waspurified by preparative LC-MS. TFA was removed using a SPE PL-HCO₃(StratoSpheres™) cartridge to afford the title compound. UPLC-MS(Condition 8) t_(R)=1.7 min, m/z=458.1 [M+H]⁺, m/z=456.2 [M−H]⁻.

Stage 145.15-Bromo-6-(1,4-diazepan-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

A mixture of 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 12.2, 198 mg, 0.50 mmol), 1,4-diazepane (60.2 mg, 0.60 mmol),iPrOH (2 mL) and DIPEA (0.171 mL, 0.129 g, 2.0 mmol) were subjected toMW irradiation 140° C. for 80 min. The vial was cooled to RT and the RMwas poured into water (40 mL) to give a suspension. The supernatant wasdecanted off and the residue was dried under vacuum to afford the titlecompound. UPLC-MS (Condition 8) t_(R)=1.15 min, m/z=459.1/461.1 [M+H]⁺,m/z=457.1/459.1 [M−H]⁻.

Example 1462-(4-Methyl-1,4-diazepan-1-yl)-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

A mixture of5-bromo-6-(4-methyl-1,4-diazepan-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 146.1, 74 mg, 0.150 mmol), pyridin-3-ylboronic acid (18.5 mg,0.150 mmol) and Na₂CO₃ (48 mg, 0.450 mmol) in a mixture of DME (3.2 mL),EtOH (0.43 mL), and water (0.64 mL) was flushed with argon. Pd(PPh₃)₂Cl₂(5.3 mg, 0.0075 mmol) was added and the mixture was subjected to MWirradiation at 125° C. for 30 min. The RM was evaporated to drynessunder reduced pressure and the residue was triturated with THF andfiltered. The filtrate was evaporated to dryness under reduced pressureand the crude product was purified by preparative LC-MS. TFA was removedusing a SPE PL-HCO₃ (StratoSpheres™ VariPure IPE) cartridge to affordthe title compound. UPLC-MS (Condition 8) t_(R)=1.71 min, m/z=472.1[M+H]⁺, m/z=470.2 [M−H]⁻.

Stage 146.15-Bromo-6-(4-methyl-1,4-diazepan-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

A mixture of 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 12.2, 198 mg, 0.50 mmol), 1-methyl-1,4-diazepane (68.6 mg, 0.60mmol), iPrOH (2 mL) and DIPEA (0.171 mL, 0.129 g, 2.0 mmol) weresubjected to MW irradiation at 140° C. for 95 min. The RM wasconcentrated under reduced pressure to afford the title compound in anequimolar mixture with DIPEA hydrochloride. UPLC-MS (Condition 8)t_(R)=1.2 min, m/z=473.1 [M+H]⁺, m/z=471.1 [M−H]⁻.

Example 1476′-Methyl-2-(4-methyl-1,4-diazepan-1-yl)-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

A mixture of5-bromo-6-(4-methyl-1,4-diazepan-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 146.1, 74 mg, 0.150 mmol), (6-methylpyridin-3-yl)boronic acid(20.6 mg, 0.150 mmol) and Na₂CO₃ (48 mg, 0.450 mmol) in a mixture of DME(3.2 mL), EtOH (0.43 mL) and water (0.64 mL) was flushed with argon.Pd(PPh₃)₂Cl₂ (5.3 mg, 0.0075 mmol) was added and the mixture wassubjected to MW irradiation at 125° C. for 30 min. The RM was evaporatedto dryness under reduced pressure and the residue was triturated withTHF and filtered. The filtrate was evaporated to dryness under reducedpressure and the crude product was purified by preparative HPLC. TFA wasremoved using a SPE PL-HCO₃ (StratoSpheres™ VariPure IPE) cartridge toafford the title compound. UPLC-MS (Condition 8) t_(R)=1.55 min,m/2z=243.6 [M+2H]⁺, m/z=484.2 [M−H]⁻.

Example 1486-Morpholino-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

5-Bromo-6-morpholino-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage148.1, 60 mg, 0.134 mmol), pyrimidin-5-ylboronic acid (50 mg, 0.403mmol), Pd(Ph₃P)₄ (12.43 mg, 10.76 μmol) and finely ground K₃PO₄ (143 mg,0.672 mmol) were added to a MW vial and treated with toluene (672 μL).The vial was sealed, evacuated/purged with argon then the RM was stirred110° C. for 16 h, diluted with DME (2 mL), treated with Si-Thiol(Silicycle, 1.44 mmol/g, 56.0 mg, 0.081 mmol), centrifuged, thesupernatant was filtered and the solvent was evaporated off underreduced pressure to give a residue which was purified by preparative SFC(Column Diol, from 15% to 20% in 6 min) to yield the title product as awhite solid. UPLC-MS (Condition 3) t_(R)=1.00 min, m/z=446.3 [M+H]⁺,m/z=444.1 [M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 3.09-3.20 (m, 4H)3.50-3.60 (m, 4H) 7.38 (d, J=8.28 Hz, 2H) 7.86 (d, J=9.16 Hz, 2H) 8.23(d, J=2.38 Hz, 1H) 8.84 (d, J=2.38 Hz, 1H) 9.13 (s, 2H) 9.22 (s, 1H)10.37 (s, 1H).

Stage 148.15-Bromo-6-morpholino-N-(4-(trifluoromethoxy)phenyl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Stage 12.1 using5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.2)and morpholine to afford an off-white solid. UPLC-MS (Condition 3)t_(R)=1.20 min, m/z=445.9 [M+H]⁺, m/z=443.9 [M−H]⁻; ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 3.37-3.46 (m, 4H) 3.69-3.81 (m, 4H) 7.39 (d, J=8.78 Hz,2H) 7.86 (d, J=9.16 Hz, 2H) 8.47 (d, J=2.13 Hz, 1H) 8.80 (d, J=2.13 Hz,1H) 10.44 (s, 1H).

Example 1496′-(Hydroxymethyl)-2-morpholino-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

5-Bromo-6-morpholino-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage148.1, 60 mg, 0.134 mmol), (6-(hydroxymethyl)pyridin-3-yl)boronic acid(41.1 mg, 0.269 mmol), Pd(PPh₃)₂Cl₂ (9.44 mg, 0.013 mmol) and Na₂CO₃(42.8 mg, 0.403 mmol) were added to a MW vial and treated with a mixtureof DME (570 μL), water (163 μL) and EtOH (81 μL). The vial was sealed,evacuated/purged with argon and subjected to MW irradiation at 125° C.for 20 min and then at 130° C. for 20 min, diluted with DME (2 mL) andtreated with Si-Thiol (Silicycle, 1.44 mmol/g, 46.7 mg, 0.067 mmol). TheRM was centrifuged, the supernatant was filtered and the solvent wasevaporated off under reduced pressure to give a residue which waspurified by preparative SFC (Column 2-EP, from 15% to 20% in 6 min) toyield the title product as a white solid. UPLC-MS (Condition 3)t_(R)=0.95 min, m/z=475.4 [M+H]⁺, m/z=473.2 [M−H]⁻; ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 3.07-3.22 (m, 4H) 3.48-3.62 (m, 4H) 4.63 (s, 2H) 5.54(br. s, 1H) 7.38 (d, J=8.53 Hz, 2H) 7.60 (d, J=8.03 Hz, 1H) 7.82-7.92(m, 2H) 8.11 (d, J=8.28 Hz, 1H) 8.13-8.16 (m, 1H) 8.75-8.79 (m, 1H)8.79-8.86 (m, 1H) 10.38 (br. s, 1H).

Example 1506-(3,7-Dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 133 using6-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-5-bromo-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 150.1) and pyrimidin-5-ylboronic acid to afford a solid. HPLC(Condition 4) t_(R)=5.08 min, UPLC-MS (Condition 3) t_(R)=1.00 min,m/z=488.2 [M+H]⁺.

Stage 150.16-(3,7-Dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-5-bromo-N-(4-(trifluoromethoxy)phenyl)nicotinamide

5-Bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.2,55.4 mg, 0.14 mmol) and 3,7-Dioxa-9-aza-bicyclo[3.3.1]nonane (OrganicChemistry (2006), 71(1), 413-415) (24.53 mg, 0.14 mmol) were dissolvedin DMF (150 μL). KF (24.4 mg, 0.42 mmol) was added and the RM mixturewas stirred at 140° C. for 18 h in a pressure safe vial. After coolingat RT, the RM was dissolved in EtOAc and washed with brine. The organicphase was dried over Na₂SO₄ and evaporated to dryness under reducedpressure to give a residue that was purified by flash chromatography(RediSep® Silica gel column, n-hexane/EtOAc from 20% to 60% EtOAc) toafford the title compound as a white solid. HPLC (Condition 4)t_(R)=5.84 min, UPLC-MS (Condition 3) t_(R)=1.19 min, m/z=490.1 [M+H]⁺.

Example 1516-((2-Hydroxyethyl)(methyl)amino)-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

5-Bromo-6-((2-hydroxyethyl)(methyl)amino)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 151.1, 59 mg, 0.136 mmol), pyrimidin-5-ylboronic acid (33.7 mg,0.272 mmol), Pd(PPh₃)₂Cl₂ (9.54 mg, 0.014 mmol) and Na₂CO₃ (57.6 mg,0.544 mmol) were added to a MW vial and treated with a mixture of DME(576 μL), water (165 μL) and EtOH (82 μL). The vial was sealed,evacuated/purged with argon and subjected to MW irradiation at 125° C.for 20 min, diluted with DME (3 mL) and treated with Si-Thiol(Silicycle, 1.44 mmol/g, 56.6 mg, 0.082 mmol). The RM was centrifuged,the supernatant was filtered and the solvent was evaporated off underreduced pressure to give a residue which was purified by preparative SFC(Column DEAP, from 10% to 15% in 10 min) to yield the title product as awhite solid. UPLC-MS (Condition 3) t_(R)=0.92 min, m/z=434.3 [M+H]⁺,m/z=432.3 [M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 2.71 (s, 3H) 3.44-3.52(m, 2H) 3.53-3.60 (m, 2H) 4.68 (t, J=5.14 Hz, 1H) 7.36 (d, J=8.41 Hz,2H) 7.82-7.90 (m, 2H) 8.15 (d, J=2.38 Hz, 1H) 8.77 (d, J=2.38 Hz, 1H)8.97 (s, 2H) 9.19 (s, 1H) 10.23 (s, 1H).

Stage 151.15-Bromo-6-((2-hydroxyethyl)(methyl)amino)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Stage 33.1 using5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.2)and 2-methylamino-ethanol to afford an off-white crystalline solid. HPLC(Condition 4) t_(R)=5.57 min, UPLC-MS (Condition 3) t_(R)=1.11 min,m/z=434.1 [M+H]⁺.

Example 1522-((2-Hydroxyethyl)(methyl)amino)-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

A mixture of5-bromo-6-((2-hydroxyethyl)(methyl)amino)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 151.1, 60 mg), pyridin-3-ylboronic acid (25 mg), 2 M Na₂CO₃ (0.2mL, 0.4 mmol) and DME (4 mL) was flushed with argon, PdCl₂(dppf)(CH₂Cl₂)(10 mg, 0.012 mmol) was added and the mixture was subjected to MWirradiation at 140° C. for 30 min. The RM was filtered through aaPL-Thiol MP SPE cartridge (StratoSpheres™, 6 mL), the cartridge waswashed with MeOH and the solvent was evaporated off under reducedpressure to give a residue which was purified by preparative LC-MS toafford the title compound. LC-MS (Condition 6) t_(R)=0.91 min, m/z=432.9[M+H]⁺.

Example 1532-((2-Hydroxyethyl)(methyl)amino)-6′-methyl-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 152 using5-bromo-6-((2-hydroxyethyl)(methyl)amino)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 151.1) and (6-methylpyridin-3-yl)boronic acid. LC-MS (Condition6) t_(R)=0.91 min, m/z=447.0 [M+H]⁺.

Example 1545′-Fluoro-2-((2-hydroxyethyl)(methyl)amino)-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 151 using5-bromo-6-((2-hydroxyethyl)(methyl)amino)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 151.1) and (5-fluoropyridin-3-yl)boronic acid to afford a whitesolid. UPLC-MS (Condition 3) t_(R)=1.04 min, m/z=451.3 [M+H]⁺, m/z=449.2[M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 2.71 (s, 3H) 3.44-3.51 (m, 2H)3.56 (q, J=5.40 Hz, 2H) 4.68 (t, J=5.14 Hz, 1H) 7.36 (d, J=8.41 Hz, 2H)7.82-7.87 (m, 2H) 7.87-7.93 (m, 1H) 8.12 (d, J=2.38 Hz, 1H) 8.58 (d,J=2.76 Hz, 1H) 8.61 (t, J=1.69 Hz, 1H) 8.75 (d, J=2.38 Hz, 1H) 10.22 (s,1H).

Example 1555′-Cyano-2-((2-hydroxyethyl)(methyl)amino)-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 151 using5-bromo-6-((2-hydroxyethyl)(methyl)amino)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 151.1) and5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile to afforda yellow wax. UPLC-MS (Condition 3) t_(R)=1.02 min, m/z=458.3 [M+H]⁺,m/z=456.3 [M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 2.69 (s, 3H) 3.47 (t,J=5.38 Hz, 2H) 3.56 (t, J=6.11 Hz, 2H) 4.34-4.84 (m, 1H) 7.36 (d, J=8.31Hz, 2H) 7.79-7.90 (m, 2H) 8.14 (d, J=2.45 Hz, 1H) 8.45 (t, J=2.08 Hz,1H) 8.77 (d, J=2.20 Hz, 1H) 9.00 (dd, J=7.21, 2.08 Hz, 2H) 10.21 (s,1H).

Example 1566-(Ethyl(2-hydroxyethyl)amino)-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 151 using5-bromo-6-(ethyl(2-hydroxyethyl)amino)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 156.1) and pyrimidin-5-ylboronic acid to afford a white solid.UPLC-MS (Condition 3) t_(R)=0.97 min, m/z=448.3 [M+H]⁺, m/z=446.3[M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 0.89 (t, J=6.96 Hz, 3H)3.11-3.16 (m, 2H) 3.34-3.41 (m, 2H) 3.49 (q, J=5.65 Hz, 2H) 4.62 (t,J=5.27 Hz, 1H) 7.36 (d, J=8.41 Hz, 2H) 7.80-7.90 (m, 2H) 8.11 (d, J=2.38Hz, 1H) 8.78 (d, J=2.26 Hz, 1H) 9.03 (s, 2H) 9.21 (s, 1H) 10.26 (s, 1H).

Stage 156.15-Bromo-6-(ethyl(2-hydroxyethyl)amino)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Stage 33.1 using5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.2)and 2-(ethylamino)ethanol to afford a white solid. (The RM was heated 18h at 140° C.). HPLC (Condition 4) t_(R)=5.92 min, UPLC-MS (Condition 3)t_(R)=1.19 min, m/z=450.1 [M+H]⁺.

Example 1572-(Ethyl(2-hydroxyethyl)amino)-5′-fluoro-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 151 using5-bromo-6-(ethyl(2-hydroxyethyl)amino)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 156.1) and (5-fluoropyridin-3-yl)boronic acid to afford a whitesolid. UPLC-MS (Condition 3) t_(R)=1.09 min, m/z=465.3 [M+H]⁺, m/z=463.4[M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 0.90 (t, J=7.03 Hz, 3H) 3.16 (q,J=7.03 Hz, 2H) 3.35-3.42 (m, 2H) 3.49 (br. s, 2H) 4.62 (br. s, 1H) 7.36(d, J=8.41 Hz, 2H) 7.80-7.89 (m, 2H) 7.98 (m, J=2.70, 1.82 Hz, 1H) 8.08(d, J=2.38 Hz, 1H) 8.60 (d, J=2.76 Hz, 1H) 8.64 (t, J=1.63 Hz, 1H) 8.76(d, J=2.38 Hz, 1H) 10.26 (s, 1H).

Example 1585′-Cyano-2-(ethyl(2-hydroxyethyl)amino)-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 151 using5-bromo-6-(ethyl(2-hydroxyethyl)amino)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 156.1) and5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile to afforda white solid. UPLC-MS (Condition 3) t_(R)=1.05 min, m/z=472.2 [M+H]⁺,m/z=470.3 [M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 0.90 (t, J=6.97 Hz,3H) 3.14 (q, J=7.01 Hz, 2H) 3.32-3.41 (m, 2H) 3.49 (q, J=5.71 Hz, 2H)4.62 (t, J=5.26 Hz, 1H) 7.36 (d, J=8.80 Hz, 2H) 7.77-7.92 (m, 2H) 8.10(d, J=2.20 Hz, 1H) 8.54 (t, J=1.96 Hz, 1H) 8.78 (d, J=2.20 Hz, 1H) 9.04(dd, J=5.50, 2.08 Hz, 2H) 10.25 (s, 1H).

Example 1592-((2-Hydroxyethyl)amino)-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 152 using5-bromo-6-((2-hydroxyethyl)amino)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 159.1) and pyridin-3-ylboronic acid. LC-MS (Condition 6)t_(R)=0.88 min, m/z=419.0 [M+H]⁺.

Stage 159.15-Bromo-6-((2-hydroxyethyl)amino)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

A mixture of 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 12.2, 0.5 g, 1.264 mmol), 2-aminoethanol hydrochloride (0.123 g,1.896 mmol), iPrOH (4 mL) and DIPEA (0.442 mL, 0.327 g, 2.53 mmol) weresubjected to MW irradiation at 140° C. for 2 h. The vial was cooled toRT and the RM was poured into water (100 mL) and the resultingprecipitate was collected by filtration. The obtained solid was washedwith water (50 mL) and dried to afford the title compound withoutfurther purification. LC-MS (Condition 6) t_(R)=1.14 min, m/z=419.8[M+H]⁺.

Example 1602-((2-Hydroxyethyl)amino)-6′-methyl-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 152 using5-bromo-6-((2-hydroxyethyl)amino)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 159.1) and (6-methylpyridin-3-yl)boronic acid. LC-MS (Condition6) t_(R)=0.87 min, m/z=433.0 [M+H]⁺.

Example 1616-((3-Hydroxypropyl)amino)-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

A mixture of5-bromo-6-((3-hydroxypropyl)amino)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 161.1, 72 mg, 0.15 mmol), pyrimidin-5-ylboronic acid (18.7 mg,0.15 mmol) and Na₂CO₃ (48 mg, 0.450 mmol) in a mixture of DME (3.2 mL),EtOH (0.43 mL) and water (0.64 mL) was flushed with argon for 5 min.Pd(PPh₃)₂Cl₂ was added (5.3 mg, 0.0075 mmol) and the mixture wassubjected to MW irradiation at 125° C. for 20 min. The vial was cooledto RT and the RM was evaporated to dryness under reduced pressure togive a residue that was triturated with THF and filtered. The filtratewas evaporated to dryness under reduced pressure and the crude productwas purified by preparative LC-MS. TFA was removed using a SPE PL-HCO₃(StratoSpheres™ VariPure IPE) cartridge to afford the title compound.UPLC-MS (Condition 8) t_(R)=2.05 min, m/z=434.1 [M+H]⁺, m/z=432.1[M−H]⁻.

Stage 161.15-Bromo-6-((3-hydroxypropyl)amino)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

A mixture of 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 12.2, 198 mg, 0.50 mmol), 3-aminopropan-1-ol (45 mg, 0.60 mmol),iPrOH (2 mL) and DIPEA (0.171 mL, 0.129 g, 1.0 mmol) were subjected toMW irradiation at 140° C. for 150 min. The vial was cooled to RT and theRM was evaporated to dryness under reduced pressure. No furtherpurification was required to afford the title compound as an equimolarmixture with DIPEA hydrochloride. UPLC-MS (Condition 8) t_(R)=1.46 min,m/z=434.0 [M+H]⁺, m/z=432.1 [M−H]⁻.

Example 1622-((3-Hydroxypropyl)amino)-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

A mixture of5-bromo-6-((3-hydroxypropyl)amino)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 161.1, 72 mg, 0.15 mmol), pyridin-3-ylboronic acid (18.6 mg, 0.15mmol) and Na₂CO₃ (48 mg, 0.450 mmol) in a mixture of DME (3.2 mL), EtOH(0.43 mL) and water (0.64 mL) was flushed with argon for 5 min.Pd(PPh₃)₂Cl₂ was added (5.3 mg, 0.0075 mmol) and the mixture subjectedto MW irradiation at 125° C. for 20 min. The vial was cooled to RT andthe RM was evaporated to dryness under reduced pressure to give aresidue that was triturated with THF and filtered. The filtrate wasevaporated to dryness under reduced pressure and the crude product waspurified by preparative LC-MS. TFA was removed using a SPE PL-HCO₃(StratoSpheres™ VariPure IPE) cartridge to afford the title compound.UPLC-MS (Condition 8) t_(R)=1.86 min, m/z=433.1 [M+H]⁺, m/z=431.1[M−H]⁻.

Example 1632-((3-Hydroxypropyl)amino)-6′-methyl-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

A mixture of5-bromo-6-((3-hydroxypropyl)amino)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 161.1, 72 mg, 0.15 mmol), (6-methylpyridin-3-yl)boronic acid(20.7 mg, 0.15 mmol) and Na₂CO₃ (48 mg, 0.450 mmol) in a mixture of DME(3.2 mL), EtOH (0.43 mL) and water (0.64 mL) was flushed with argon for5 min. Pd(PPh₃)₂Cl₂ was added (5.3 mg, 0.0075 mmol) and the mixturesubjected to MW irradiation at 125° C. for 20 min. The vial was cooledto RT and the RM was evaporated to dryness under reduced pressure togive a residue that was triturated with THF and filtered. The filtratewas evaporated to dryness under reduced pressure and the crude productwas purified by preparative LC-MS. TFA was removed using a SPE PL-HCO₃(StratoSpheres™ VariPure IPE) cartridge to afford the title compound.UPLC-MS (Condition 8) t_(R)=1.87 min, m/z=447.1 [M+H]⁺, m/z=445.2[M−H]⁻.

Example 1642-((3-Hydroxypropyl)amino)-6′-methoxy-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

A mixture of5-bromo-6-((3-hydroxypropyl)amino)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 161.1, 72 mg, 0.15 mmol), (6-methoxypyridin-3-yl)boronic acid(23.1 mg, 0.15 mmol) and Na₂CO₃ (48 mg, 0.450 mmol) in a mixture of DME(3.2 mL), EtOH (0.43 mL) and water (0.64 mL) was flushed with argon for5 min. Pd(PPh₃)₂Cl₂ was added (5.3 mg, 0.0075 mmol) and the mixturesubjected to MW irradiation at 125° C. for 20 min. The vial was cooledto RT and the RM was evaporated to dryness under reduced pressure togive a residue that was triturated with THF and filtered. The filtratewas evaporated to dryness under reduced pressure and the crude productwas purified by preparative LC-MS. TFA was removed using a SPE PL-HCO₃(StratoSpheres™ VariPure IPE) cartridge to afford the title compound.UPLC-MS (Condition 8) t_(R)=2.33 min, m/z=463.1 [M+H]⁺, m/z=461.1[M−H]⁻.

Example 1656-((3-Hydroxypropyl)(methyl)amino)-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

A mixture of5-bromo-6-((3-hydroxypropyl)(methyl)amino)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 165.1, 90 mg, 0.185 mmol), pyrimidin-5-ylboronic acid (22.9 mg,0.185 mmol) and Na₂CO₃ (59 mg, 0.554 mmol) in a mixture of DME (4.0 mL),EtOH (0.54 mL) and water (0.80 mL) was flushed with argon for 5 min.Pd(PPh₃)₂Cl₂ was added (6.5 mg, 0.0092 mmol) and the mixture wassubjected to MW irradiation at 125° C. for 20 min. The vial was cooledto RT and the RM was evaporated to dryness under reduced pressure togive a residue that was triturated with THF and filtered. The filtratewas evaporated to dryness under reduced pressure and the crude productwas purified by preparative LC-MS. TFA was removed using a SPE PL-HCO₃(StratoSpheres™ VariPure IPE) cartridge to afford the title compound.UPLC-MS (Condition 8) t_(R)=2.26 min, m/z=448.1 [M+H]⁺, m/z=446.2[M−H]⁻.

Stage 165.15-Bromo-6-((3-hydroxypropyl)(methyl)amino)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

A mixture of 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 12.2, 237 mg, 0.60 mmol), 3-(methylamino)propan-1-ol (64 mg, 0.72mmol), iPrOH (2.4 mL) and DIPEA (0.205 mL, 0.155 g, 1.2 mmol) weresubjected to MW irradiation at 140° C. for 3 h. The vial was cooled toRT and the RM was evaporated to dryness under reduced pressure. Nofurther purification was required to afford the title compound in anequimolar mixture with DIPEA hydrochloride. LC-MS (Condition 5)t_(R)=1.18 min, m/z=448.0 [M+H]⁺, m/z=446.0 [M−H]⁻.

Example 1662-((3-Hydroxypropyl)(methyl)amino)-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

A mixture of5-bromo-6-((3-hydroxypropyl)(methyl)amino)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 165.1, 90 mg, 0.185 mmol), pyridin-3-ylboronic acid (22.7 mg,0.185 mmol) and Na₂CO₃ (59 mg, 0.554 mmol) in a mixture of DME (4.0 mL),EtOH (0.54 mL) and water (0.80 mL) was flushed with argon for 5 min.Pd(PPh₃)₂Cl₂ was added (6.5 mg, 0.0092 mmol) and the mixture wassubjected to MW irradiation at 125° C. for 20 min. The vial was cooledto RT and the RM was evaporated to dryness under reduced pressure togive a residue that was triturated with THF and filtered. The filtratewas evaporated to dryness under reduced pressure and the crude productwas purified by preparative LC-MS. TFA was removed using a SPE PL-HCO₃(StratoSpheres™ VariPure IPE) cartridge to afford the title compound.UPLC-MS (Condition 8) t_(R)=2.05 min, m/z=447.1 [M+H]⁺, m/z=445.2[M−H]⁻.

Example 1672-((3-Hydroxypropyl)(methyl)amino)-6′-methyl-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

A mixture of5-bromo-6-((3-hydroxypropyl)(methyl)amino)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 165.1, 92 mg, 0.189 mmol), (6-methylpyridin-3-yl)boronic acid(25.9 mg, 0.189 mmol) and Na₂CO₃ (60 mg, 0.566 mmol) in a mixture of DME(4.0 mL), EtOH (0.54 mL) and water (0.80 mL) was flushed with argon for5 min. Pd(PPh₃)₂Cl₂ was added (6.6 mg, 0.0094 mmol) and the mixturesubjected to MW irradiation at 125° C. for 20 min. The vial was cooledto RT and the RM was evaporated to dryness under reduced pressure togive a residue that was triturated with THF and filtered. The filtratewas evaporated to dryness under reduced pressure and the crude productwas purified by preparative LC-MS. TFA was removed using a SPE PL-HCO₃(StratoSpheres™ VariPure IPE) cartridge. Additional purification(Isolute Flash Silica gel cartridge, 5 g, elution of impurities withEtOAc, subsequent elution of product with MeOH) afforded the titlecompound. LC-MS (Condition 5) t_(R)=1.65 min, m/z=461.2 [M+H]⁺,m/z=459.2 [M−H]⁻.

Example 1682-((3-(Dimethylamino)propyl)(methyl)amino)-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

A mixture of5-bromo-6-((3-(dimethylamino)propyl)(methyl)amino)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 165.1, 88 mg, 0.185 mmol), pyridin-3-ylboronic acid (22.7 mg,0.185 mmol) and Na₂CO₃ (59 mg, 0.555 mmol) in a mixture of DME (4.0 mL),EtOH (0.54 mL) and water (0.80 mL) was flushed with argon for 5 min.Pd(PPh₃)₂Cl₂ was added (6.5 mg, 0.0093 mmol) and the mixture wassubjected to MW irradiation at 125° C. (MW irradiation) for 30 min.Additional pyridin-3-ylboronic acid (22.7 mg, 0.185 mmol), Na₂CO₃ (59mg, 0.555 mmol) and Pd(PPh₃)₂Cl₂ (6.5 mg, 0.0093 mmol) were added andthe mixture stirred at 125° C. for further 30 min. The vial was cooledto RT and the RM was evaporated to dryness under reduced pressure togive a residue that was triturated with THF and filtered. The filtratewas evaporated to dryness under reduced pressure and the crude productwas purified by preparative LC-MS. TFA was removed using a SPE PL-HCO₃(StratoSpheres™ VariPure IPE) cartridge to afford the title compound.LC-MS (Condition 6) t_(R)=1.33 min, m/z=474.0 [M+H]⁺.

Stage 168.15-Bromo-6-((3-(dimethylamino)propyl)(methyl)amino)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

A mixture of 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 12.2, 237 mg, 0.60 mmol), N1,N1,N3-trimethylpropane-1,3-diamine(84 mg, 0.72 mmol), iPrOH (2.4 mL) and DIPEA (0.205 mL, 0.155 g, 1.2mmol) were subjected to MW irradiation at 140° C. for 120 min. The vialwas cooled to RT and the RM was evaporated to dryness under reducedpressure. No further purification was required to afford the titlecompound in an equimolar mixture with DIPEA hydrochloride. UPLC-MS(Condition 8) t_(R)=2.18 min, m/z=475.1 [M+H]⁺, m/z=473.1 [M−H]⁻.

Example 169

(S)—N-(4-(Chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5-(pyrimidin-5-yl)nicotinamide

(S)-5-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide(Stage 169.1, (116 mg, 0.25 mmol) and pyrimidin-5-ylboronic acid (62 mg,0.5 mmol) were dissolved in DME (1 mL). A solution of 2 M Na₂CO₃ (0.375mL, 0.75 mmol) was added, the mixture was flushed with argon,PdCl₂(dppf) (9 mg, 0.013 mmol) was added and the RM subjected to MWirradiation at 100° C. for 2 h. After cooling to RT, the RM wasdissolved in EtOAc and washed with brine. The organic phase was driedover Na₂SO₄ and evaporated under reduced pressure to give a residue thatwas purified flash chromatography (RediSep® Silica gel column,EtOAc/EtOAc-MeOH (98:2)), from 50% to 100% EtOAc-MeOH (98:2)) andtreated with Si-Thiol (80 mg) in MeOH to afford the title compound as awhite crystalline powder. HPLC (Condition 4) t_(R)=4.71 min, HPLC Chiral(CHIRALPAK® AD-H, 250×4.6 mm, eluent: EtOH/MeOH (50:50), 0.5 mL/min, UV210 nm) t_(R)=60.52 min, UPLC-MS (Condition 3) t_(R)=0.95 min, m/z=462.2[M+H]⁺; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.68-1.78 (m, 1H) 1.80-1.90 (m,1H) 2.82-2.92 (m, 1H) 3.15-3.26 (m, 2H) 3.33-3.41 (m, 1H) 4.15-4.24 (m,1H) 4.86 (d, J=3.52 Hz, 1H) 7.33 (d, J=8.21 Hz, 2H) 7.84 (d, J=9.38 Hz,2H) 8.03-8.13 (m, 1H) 8.78 (m, J=2.35, 0.78 Hz, 1H) 8.87 (s, 2H) 9.18(d, J=0.78 Hz, 1H) 10.16 (s, 1H).

Stage 169.1(S)-5-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide

DIPEA (190 μL, 1.1 mmol) was added to a solution of5-bromo-6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide (Stage169.2, 206 mg, 0.5 mmol) and (S)-pyrrolidin-3-ol (52.3 mg, 0.6 mmol) iniPrOH (500 μL) in a vial, which was sealed and heated at 140° C. for 1h. After cooling at RT, the RM was dissolved in EtOAc, washed with 0.5 Maq. HCl and brine, dried over Na₂SO₄ and the solvent was evaporated offunder reduced pressure to give the crude product which was purified byflash chromatography (RediSep® Silica gel column, n-heptane/EtOAc, from20% to 100% EtOAc) to afford the title compound as a white crystallinepowder. HPLC (Condition 4) t_(R)=5.59 min, UPLC-MS (Condition 3)t_(R)=1.17 min, m/z=462.0/464.1 [M+H]⁺.

Stage 169.25-Bromo-6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-nicotinamide

5-Bromo-6-chloro-nicotinic acid (8 g, 33.8 mmol) was suspended intoluene (70 mL). DMF (0.77 mL, 10.15 mmol) was added followed by slowaddition of SOCl₂ (7.4 mL, 102 mmol) and the RM was stirred for 1 h at80° C. After cooling at RT, the toluene was evaporated off under reducepressure. The residue was dissolved in THF (70 mL) and cooled to −10-15°C. and treated with DIPEA (11.8 mL, 67.7 mmol) followed by the slowaddition of a solution of 4-(chloro-difluoro-methoxy)aniline (6.88 g,35.5 mmol) in THF (70 mL) over 10 min. The RM was allowed to warm at RTand stirred for 1 h, the solvent was evaporated off under reducedpressure. The residue was dissolved in TBME, the solution was washedwith 1 M HCl, 10% aq. NaHCO₃ and brine, dried over Na₂SO₄ andconcentrated under reduced pressure until crystallisation started.n-Heptane was then added and the product was filtered and dried toafford the title compound as a beige crystalline powder. HPLC (Condition4) t_(R)=6.46 min, UPLC-MS (Condition 3) t_(R)=1.29 min, m/z=411 [M+H]⁺.

Example 170(R)—N-(4-(Chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5-(pyrimidin-5-yl)nicotinamide

(R)-6-(3-Hydroxypyrrolidin-1-yl)-5-(pyrimidin-5-yl)nicotinic acid (Stage170.1, 57.3 mg, 0.2 mmol), HOBT (43.5, 0.284 mmol) and EDC (42.2 mg,0.22 mmol) were dissolved in 0.3 M NMM in DMF (0.8 mL) at RT.4-(Chlorodifluoromethoxy)aniline (36.8 mg, 0.19 mmol) was added and theRM was stirred for 5 h. The RM was then diluted with EtOAc and washedwith 10% NaHCO₃. The organic layer was dried over Na₂SO₄, filtered andevaporated to dryness under reduced pressure. The residue was purifiedby flash chromatography (RediSep® Silica gel column, DCM/MeOH, from 2 to5% MeOH) and treated with Si-Thiol (50 mg) in MeOH to afford the titlecompound. HPLC Chiral (CHIRALPAK® AD-H, 250×4.6 mm, eluent: EtOH/MeOH(50:50), 0.5 mL/min, UV 210 nm) t_(R)=21.89 min, UPLC-MS (Condition 3)t_(R)=0.95 min, m/z=462.2/464.2 [M+H]⁺; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm1.67-1.78 (m, 1H) 1.80-1.89 (m, 1H) 2.87 (d, J=11.34 Hz, 1H) 3.21 (m,J=11.10, 4.90 Hz, 2H) 3.33-3.44 (m, 1H) 4.12-4.24 (m, 1H) 4.87 (d,J=3.52 Hz, 1H) 7.33 (d, J=8.60 Hz, 2H) 7.77-7.89 (m, 2H) 8.08 (d, J=2.35Hz, 1H) 8.78 (d, J=2.35 Hz, 1H) 8.88 (s, 2H) 9.18 (s, 1H) 10.17 (s, 1H).

Stage 170.1 (R)-6-(3-Hydroxypyrrolidin-1-yl)-5-(pyrimidin-5-yl)nicotinicacid

(R)-Methyl 6-(3-hydroxypyrrolidin-1-yl)-5-(pyrimidin-5-yl)nicotinate(Stage 170.2, 640 mg, 4.26 mmol) was added to 2 M NaOH (2 mL) andstirred 30 min at RT until complete dissolution. The RM was acidified(pH=2) with 2 M HCl and the solid which precipitated was filtered toafford the title compound as a white crystalline powder. HPLC (Condition4) t_(R)=2.19 min, UPLC-MS (Condition 7) m/z=287.1 [M+H]⁺.

Stage 170.2 (R)-Methyl6-(3-hydroxypyrrolidin-1-yl)-5-(pyrimidin-5-yl)nicotinate

(R)-Methyl 5-bromo-6-(3-hydroxypyrrolidin-1-yl)nicotinate (Stage 170.3,930 mg, 3.1 mmol) and pyrimidin-5-ylboronic acid (765 mg, 6.2 mmol) weredissolved in a solution of DME (5 mL) and EtOH (0.7 mL). A solution of 2M Na₂CO₃ (4.63 mL, 9.26 mmol) was added, the mixture was flushed withargon, Pd(PPh₃)₂Cl₂ (260 mg, 0.371 mmol) was added and the RM wasstirred at 95° C. in a pressure safe vial for 1.5 h. After cooling atRT, the RM was treated with brine and extracted with EtOAc. The combinedextracts were dried over Na₂SO₄ and the solvent was evaporated off underreduced pressure to give a residue that was purified by flashchromatography (RediSep® Silica gel column, (DCM/MeOH 98:2)/MeOH, from 0to 5% MeOH) a treated with Si-Thiol (1 g) in MeOH to afford the titlecompound as a grey foamy powder. HPLC (Condition 4) t_(R)=2.95 min,UPLC-MS (Condition 7) m/z=301.1 [M+H]⁺.

Stage 170.3 (R)-Methyl 5-bromo-6-(3-hydroxypyrrolidin-1-yl)nicotinate

Methyl-5-bromo-6-chroronicotinate (1 g, 4 mmol) and (R)-pyrrolidin-3-ol(418 mg, 4.8 mmol) were dissolved in iPrOH (4 mL). DIPEA (0.9 mL, 5.2mmol) was added and the RM mixture was heated at 140° C. for 1 h. Aftercooling at RT, the RM was dissolved in EtOAc and washed with brine. Theorganic phase was dried over Na₂SO₄ and the solvent was evaporated offunder reduced pressure to give a residue that was purified by flashchromatography (RediSep® Silica gel column, n-hexane/EtOAc, from 50% to80% EtOAc) to afford the title compound as a brown-yellow oil. HPLC(Condition 4) t_(R)=4.11 min, UPLC-MS (Condition 7) m/z=301 [M+H]⁺.

Example 171(R)—N-(4-(Chlorodifluoromethoxy)phenyl)-5′-fluoro-2-(3-hydroxypyrrolidin-1-yl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 151 using(R)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide(Stage 171.1) and (5-fluoropyridin-3-yl)boronic acid to afford a whitesolid. UPLC-MS (Condition 3) t_(R)=1.03 min, m/z=479.1 [M+H]⁺, m/z=523.0[M+formic acid−H]; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.68-1.79 (m, 1H)1.80-1.91 (m, 1H) 2.87 (d, J=11.17 Hz, 1H) 3.17-3.29 (m, 2H) 3.35-3.45(m, 1H) 4.20 (br. s, 1H) 4.89 (d, J=2.51 Hz, 1H) 7.35 (d, J=9.16 Hz, 2H)7.82-7.89 (m, 3H) 8.08 (d, J=2.38 Hz, 1H) 8.51 (t, J=1.63 Hz, 1H) 8.60(d, J=2.76 Hz, 1H) 8.78 (d, J=2.38 Hz, 1H) 10.20 (s, 1H).

Stage 171.1(R)-5-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide

5-Bromo-6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide (Stage169.2, 206 mg, 0.5 mmol) and (R)-pyrrolidin-3-ol (52.3 mg, 0.6 mmol)were dissolved in iPrOH (1 mL). DIPEA (192 μL, 1.1 mmol) was added andthe RM mixture was stirred at 140° C. for 1 h in a sealed vial. Aftercooling at RT, the RM was dissolved in EtOAc, washed with 0.5 M HCl andbrine, dried over Na₂SO₄ and the solvent was evaporated off underreduced pressure to give a crude product which was purified by flashchromatography (RediSep® Silica gel column, n-heptane/EtOAc from 20% to100% EtOAc). The resulting product was triturated under n-heptane,filtered and dried to afford the title compound as a white crystallinepowder. HPLC (Condition 4) t_(R)=5.68 min, UPLC-MS (Condition 3)t_(R)=1.15 min, m/z=462.1 [M+H]⁺.

Example 172(R)—N-(4-(Chlorodifluoromethoxy)phenyl)-2′-fluoro-2-(3-hydroxypyrrolidin-1-yl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 133 using(R)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide(Stage 171.1) and (2-fluoropyridin-3-yl)boronic acid to afford a whitesolid. HPLC (Condition 4) t_(R)=5.22 min, UPLC-MS (Condition 3)t_(R)=1.07 min, m/z=479.3 [M+H]⁺; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm1.63-1.76 (m, 1H) 1.78-1.88 (m, 1H) 2.84-2.97 (m, 1H) 3.15 (m, J=4.70Hz, 2H) 3.31-3.43 (m, 1H) 4.14-4.24 (m, 1H) 4.86 (br. s, 1H) 7.32 (d,J=8.99 Hz, 2H) 7.42-7.54 (m, 1H) 7.76-7.89 (m, 2H) 8.00 (d, J=2.35 Hz,1H) 8.03-8.13 (m, 1H) 8.28 (d, J=4.69 Hz, 1H) 8.78 (d, J=2.35 Hz, 1H)10.15 (s, 1H).

Example 173(R)—N-(4-(Chlorodifluoromethoxy)phenyl)-5′-cyano-2-(3-hydroxypyrrolidin-1-yl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 151 using(R)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide(Stage 171.1) and5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile to afforda white solid. UPLC-MS (Condition 3) t_(R)=1.02 min, m/z=486.2 [M+H]⁺,m/z=530.0 [M+formic acid−H]; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.69-1.80(m, 1H) 1.80-1.91 (m, 1H) 2.85 (d, J=11.42 Hz, 1H) 3.16-3.26 (m, 2H)3.35-3.43 (m, 1H) 4.20 (br. s, 1H) 4.90 (d, J=3.64 Hz, 1H) 7.35 (d,J=9.16 Hz, 2H) 7.82-7.89 (m, 2H) 8.10 (d, J=2.38 Hz, 1H) 8.41 (t, J=2.07Hz, 1H) 8.79 (d, J=2.38 Hz, 1H) 8.90 (d, J=2.26 Hz, 1H) 9.03 (d, J=1.88Hz, 1H) 10.20 (s, 1H).

Example 174(S)—N-(4-(Chlorodifluoromethoxy)phenyl)-6-(3-(hydroxymethyl)pyrrolidin-1-yl)-5-(pyrimidin-5-yl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 169 using(S)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-(hydroxymethyl)pyrrolidin-1-yl)nicotinamide(Stage 174.1) and pyrimidin-5-ylboronic acid to afford a white solid.HPLC (Condition 4) t_(R)=4.93 min, UPLC-MS (Condition 3) t_(R)=0.97 min,m/z=476.3 [M+H]⁺; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.57 (m, J=12.10, 7.80Hz, 1H) 1.84 (m, J=11.90, 6.10 Hz, 1H) 2.12-2.31 (m, 1H) 2.95 (dd,J=10.56, 7.04 Hz, 1H) 3.08-3.44 (m, 5H) 4.60 (t, J=5.08 Hz, 1H) 7.33 (d,J=8.21 Hz, 2H) 7.84 (d, J=9.38 Hz, 2H) 8.07 (d, J=2.35 Hz, 1H) 8.78 (d,J=2.35 Hz, 1H) 8.88 (s, 2H) 9.17 (s, 1H) 10.16 (s, 1H).

Stage 174.1(S)-5-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-(hydroxymethyl)pyrrolidin-1-yl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Stage 33.1 using5-bromo-6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide (Stage169.2) and (S)-1-pyrrolidin-3-yl-methanol to afford an off-whitecrystalline solid. HPLC (Condition 4) t_(R)=5.82 min, UPLC-MS (Condition3) t_(R)=1.14 min, m/z=476.2/478.3 [M+H]⁺.

Example 175(S)—N-(4-(Chlorodifluoromethoxy)phenyl)-5′-fluoro-2-(3-(hydroxymethyl)pyrrolidin-1-yl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 169 using(S)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-(hydroxymethyl)pyrrolidin-1-yl)nicotinamide(Stage 174.1) and3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine toafford an off-white solid. HPLC (Condition 4) t_(R)=5.29 min, UPLC-MS(Condition 3) t_(R)=1.06 min, m/z=493.3 [M+H]⁺; ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 1.47-1.63 (m, 1H) 1.83 (m, J=5.90 Hz, 1H) 2.14-2.28 (m,1H) 2.96 (dd, J=10.95, 7.04 Hz, 1H) 3.10-3.38 (m, 5H) 4.60 (t, J=5.08Hz, 1H) 7.32 (d, J=8.21 Hz, 2H) 7.77-7.88 (m, 3H) 8.05 (d, J=1.00 Hz,1H) 8.50 (s, 1H) 8.57 (d, J=1.96 Hz, 1H) 8.76 (d, J=1.00 Hz, 1H) 10.16(s, 1H).

Example 176(S)—N-(4-(Chlorodifluoromethoxy)phenyl)-5′-cyano-2-(3-(hydroxymethyl)pyrrolidin-1-yl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 151 using(S)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-(hydroxymethyl)pyrrolidin-1-yl)nicotinamide(Stage 174.1) and5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile to afforda yellow solid. UPLC-MS (Condition 3) t_(R)=1.05 min, m/z=498.5 [M+H]⁺,m/z=500.0 [M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.51-1.66 (m, 1H)1.78-1.92 (m, 1H) 2.17-2.30 (m, 1H) 2.96 (dd, J=11.00, 6.85 Hz, 1H)3.11-3.28 (m, 4H) 3.32-3.42 (m, 1H) 4.60 (t, J=5.26 Hz, 1H) 7.34 (d,J=9.05 Hz, 2H) 7.81-7.91 (m, 2H) 8.08 (d, J=2.20 Hz, 1H) 8.40 (t, J=2.08Hz, 1H) 8.79 (d, J=2.45 Hz, 1H) 8.91 (d, J=2.20 Hz, 1H) 9.01 (d, J=1.96Hz, 1H) 10.16 (s, 1H).

Example 177(S)-6-(3-(Aminomethyl)pyrrolidin-1-yl)-N-(4-(chlorodifluoromethoxy)phenyl)-5-(pyrimidin-5-yl)nicotinamide

(S)-Tert-Butyl((1-(3-bromo-5-((4-(chlorodifluoromethoxy)phenyl)carbamoyl)-pyridin-2-yl)pyrrolidin-3-yl)methyl)carbamate(Stage 177.1, 120 mg, 0.209 mmol) was dissolved in DCM (1.0 mL), TFA(0.5 mL) was added and stirred at 0° C. for 1 h. The RM was poured into25 mL of Na₂CO₃ 10%, then extracted with EtOAc. The combined extractswere dried over Na₂SO₄ and evaporated to dryness under reduced pressureto afford the title compound as an off-white solid. HPLC (Condition 4)t_(R)=4.24 min, UPLC-MS (Condition 3) t_(R)=0.80 min, m/z=475.3 [M+H]⁺;¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.46-1.63 (m, 1H) 1.81-1.97 (m, 1H)2.10-2.21 (m, 1H) 2.57 (m, J=7.40, 7.40 Hz, 2H) 2.91-3.03 (m, 1H)3.07-3.17 (m, 2H) 3.30 (s, 3H) 7.33 (d, J=8.99 Hz, 2H) 7.78-7.89 (m, 2H)8.09 (d, J=2.35 Hz, 1H) 8.77 (d, J=2.35 Hz, 1H) 8.88 (s, 2H) 9.18 (s,1H) 10.16 (s, 1H).

Stage 177.1 (S)-tert-Butyl(0-(3-bromo-5-((4-(chlorodifluoromethoxy)phenyl)-carbamoyl)pyridin-2-yl)pyrrolidin-3-yl)methyl)carbamate

The title compound was prepared in an analogous fashion to thatdescribed in Example 169 using5-bromo-6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide (Stage169.2) and (R)-1-pyrrolidin-3-ylmethyl-carbamic acid tert-butyl ester toafford a crystalline solid. HPLC (Condition 4) t_(R)=6.09 min, UPLC-MS(Condition 3) t_(R)=1.36 min, m/z=577.2 [M+H]⁺.

Example 178(R)-6-(3-(Acetamidomethyl)pyrrolidin-1-yl)-N-(4-(chlorodifluoromethoxy)phenyl)-5-(pyrimidin-5-yl)nicotinamide

(S)-6-(3-(Aminomethyl)pyrrolidin-1-yl)-N-(4-(chlorodifluoromethoxy)phenyl)-5-(pyrimidin-5-yl)nicotinamide(Example 177, 30 mg, 0.063 mmol) was dissolved in dioxane (0.5 mL),acetic anhydride (7.09 mg, 0.069 mmol) was added and the RM was stirredfor 3 h at RT. The RM was poured into 15 mL of Na₂CO₃ 10%, thenextracted with EtOAc. The combined organic layers were dried over Na₂SO₄and evaporated to dryness under reduced pressure, dissolved in MeOH,evaporated and dried under HV to afford the title compound as anoff-white solid. HPLC (Condition 4) t_(R)=4.95 min, UPLC-MS (Condition3) t_(R)=0.93 min, m/z=517.3 [M+H]⁺; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm1.44-1.60 (m, 1H) 1.75 (s, 3H) 1.79-1.93 (m, 1H) 2.15-2.31 (m, 1H)2.86-3.02 (m, 3H) 3.04-3.20 (m, 2H) 3.23-3.36 (m, 1H) 7.33 (d, J=8.21Hz, 2H) 7.77-7.93 (m, 3H) 8.08 (d, J=2.35 Hz, 1H) 8.77 (d, J=0.78 Hz,1H) 8.87 (s, 2H) 9.17 (s, 1H) 10.16 (s, 1H).

Example 179N-(4-(Chlorodifluoromethoxy)phenyl)-6-((2-hydroxyethyl)(methyl)amino)-5-(pyrimidin-5-yl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 169 using5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-((2-hydroxyethyl)(methyl)amino)nicotinamide(Stage 179.1) and pyrimidin-5-ylboronic acid to afford a whitecrystalline solid. HPLC (Condition 4) t_(R)=5.02 min, UPLC-MS (Condition3) t_(R)=0.96 min, m/z=450.3 [M+H]⁺; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm2.69 (s, 3H) 3.38-3.65 (m, 4H) 4.67 (t, J=5.08 Hz, 1H) 7.34 (d, J=8.21Hz, 2H) 7.85 (d, J=8.99 Hz, 2H) 8.13 (d, J=2.35 Hz, 1H) 8.75 (d, J=1.56Hz, 1H) 8.95 (s, 2H) 9.17 (s, 1H) 10.22 (s, 1H).

Stage 179.15-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-((2-hydroxyethyl)(methyl)amino)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Stage 33.1 using5-bromo-6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide (Stage169.2) and 2-methylamino-ethanol to afford as a white crystalline solid.HPLC (Condition 4) t_(R)=5.72 min, UPLC-MS (Condition 3) t_(R)=1.14 min,m/z=452.2 [M+H]⁺.

Example 180N-(4-(Chlorodifluoromethoxy)phenyl)-5′-fluoro-2-((2-hydroxyethyl)(methyl)amino)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 169 using5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-((2-hydroxyethyl)(methyl)amino)nicotinamide(Stage 179.1) and3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine toafford an off-white foam. HPLC (Condition 4) t_(R)=5.51 min, UPLC-MS(Condition 3) t_(R)=1.07 min, m/z=467.3 [M+H]⁺; ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 2.69 (s, 3H) 3.39-3.61 (m, 4H) 4.65 (t, J=5.08 Hz, 1H)7.33 (d, J=8.99 Hz, 2H) 7.77-7.94 (m, 3H) 8.11 (d, J=2.35 Hz, 1H)8.50-8.63 (m, 2H) 8.74 (d, J=2.35 Hz, 1H) 10.21 (s, 1H).

Example 181N-(4-(Chlorodifluoromethoxy)phenyl)-5′-cyano-2-((2-hydroxyethyl)(methyl)amino)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 151 using5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-((2-hydroxyethyl)(methyl)amino)nicotinamide(Stage 179.1) and5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile to afforda yellow solid. UPLC-MS (Condition 3) t_(R)=1.05 min, m/z=474.3 [M+H]⁺,m/z=472.3 [M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 2.70 (s, 3H) 3.48 (d,J=5.38 Hz, 2H) 3.56 (d, J=5.38 Hz, 2H) 4.66 (br. s, 1H) 7.36 (d, J=9.05Hz, 2H) 7.81-7.93 (m, 2H) 8.15 (d, J=2.45 Hz, 1H) 8.46 (t, J=2.08 Hz,1H) 8.77 (d, J=2.20 Hz, 1H) 9.01 (dd, J=7.21, 2.08 Hz, 2H) 10.23 (s,1H).

Example 182N-(4-(Chlorodifluoromethoxy)phenyl)-6-(ethyl(2-hydroxyethyl)amino)-5-(pyrimidin-5-yl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 169 using5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(ethyl(2-hydroxyethyl)amino)nicotinamide(Stage 182.1) and pyrimidin-5-ylboronic acid to afford a light yellowfoam. HPLC (Condition 4) t_(R)=5.23 min, UPLC-MS (Condition 3)t_(R)=1.01 min, m/z=464.3 [M+H]⁺; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 0.87(t, J=6.84 Hz, 3H) 3.14 (m, J=7.00 Hz, 2H) 3.32-3.54 (m, 4H) 4.61 (t,J=5.28 Hz, 1H) 7.34 (d, J=8.21 Hz, 2H) 7.84 (d, J=1.00 Hz, 2H) 8.10 (dd,J=2.35, 1.17 Hz, 1H) 8.77 (dd, J=2.35, 1.17 Hz, 1H) 9.01 (d, J=0.78 Hz,2H) 9.19 (d, J=1.17 Hz, 1H) 10.26 (s, 1H).

Stage 182.15-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(ethyl(2-hydroxyethyl)amino)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Stage 33.1 using5-bromo-6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide (Stage169.2) and 2-ethylamino-ethanol to afford an off-white crystallinesolid. (Reaction Time was 10 h). HPLC (Condition 4) t_(R)=6.1 min,UPLC-MS (Condition 3) t_(R)=1.21 min, m/z=466.2 [M+H]⁺.

Example 183N-(4-(Chlorodifluoromethoxy)phenyl)-2-(ethyl(2-hydroxyethyl)amino)-5′-fluoro-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 169 using5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(ethyl(2-hydroxyethyl)amino)nicotinamide(Stage 182.1) and3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine toafford an off-white foam. HPLC (Condition 4) t_(R)=5.71 min, UPLC-MS(Condition 3) t_(R)=1.11 min, m/z=481.3 [M+H]⁺; ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 0.88 (t, J=6.84 Hz, 3H) 3.15 (m, J=7.00 Hz, 2H) 3.32-3.41(m, 2H) 3.42-3.52 (m, 2H) 4.61 (t, J=5.08 Hz, 1H) 7.33 (d, J=8.60 Hz,2H) 7.83 (d, J=0.78 Hz, 2H) 7.95 (d, J=1.17 Hz, 1H) 8.06 (d, J=1.00 Hz,1H) 8.52-8.66 (m, 2H) 8.75 (d, J=2.74 Hz, 1H) 10.25 (s, 1H).

Example 184N-(4-(Chlorodifluoromethoxy)phenyl)-5′-cyano-2-(ethyl(2-hydroxyethyl)amino)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 151 using5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(ethyl(2-hydroxyethyl)amino)nicotinamide(Stage 182.1) and5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile to afforda yellow solid. UPLC-MS (Condition 3) t_(R)=1.10 min, m/z=486.3 [M+H]⁺,m/z=488.3 [M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 0.90 (t, J=6.97 Hz,3H) 3.15 (q, J=7.09 Hz, 2H) 3.37 (t, J=5.99 Hz, 2H) 3.44-3.55 (m, 2H)4.62 (br. s, 1H) 7.36 (d, J=9.29 Hz, 2H) 7.82-7.90 (m, 2H) 8.11 (d,J=2.45 Hz, 1H) 8.54 (t, J=2.08 Hz, 1H) 8.79 (d, J=2.45 Hz, 1H) 9.04 (dd,J=5.62, 1.96 Hz, 2H) 10.26 (s, 1H).

Example 185(S)-6-(3-Hydroxypyrrolidin-1-yl)-5-(pyrimidin-5-yl)-N-(4-((trifluoromethyl)thio)phenyl)nicotinamide

(S)-5-Bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-((trifluoromethyl)thio)phenyl)nicotinamide(Stage 185.1, 116 mg, 0.25 mmol) and pyrimidin-5-ylboronic acid (62 mg,0.5 mmol) were dissolved in DME (1 mL). A solution of 2 M NaHCO₃ (0.375mL, 0.75 mmol) was added, the mixture was flushed with argon, heated to100° C. in a pressure safe vial and PdCl₂(dppf) (9.15 mg, 0.013 mmol)was added. The RM was stirred under argon at 100° C. for 2 h. The RM wascooled to RT, diluted with EtOAc and washed with brine. The organiclayer was dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by flash chromatography (RediSep®Silica gel column, EtOAc/(EtOAc/MeOH 98:2), 50% to 100% (EtOAc/MeOH98:2) and treated with Si-Thiol (80 mg) in MeOH to afford the titlecompound as a white powder. HPLC (Condition 4) t_(R)=5.03 min, HPLCChiral (CHIRALPAK® AD-H, 250×4.6 mm, 5 μm, eluent: EtOH/MeOH (50:50), 1mL/min, UV 220 nm, t_(R)=24.83 min, UPLC-MS (Condition 3) t_(R)=0.99min, m/z=462.2 [M+H]⁺; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.67-1.78 (m, 1H)1.80-1.90 (m, 1H) 2.88 (d, J=11.34 Hz, 1H) 3.21 (m, J=10.90, 4.70 Hz,2H) 3.33-3.43 (m, 1H) 4.20 (d, J=1.96 Hz, 1H) 4.87 (d, J=3.52 Hz, 1H)7.68 (d, J=8.60 Hz, 2H) 7.90 (d, J=8.99 Hz, 2H) 8.09 (d, J=2.35 Hz, 1H)8.79 (d, J=2.35 Hz, 1H) 8.88 (s, 2H) 9.18 (s, 1H) 10.26 (s, 1H).

Stage 185.1(S)-5-Bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-((trifluoromethyl)thio)phenyl)nicotinamide

5-Bromo-6-chloro-N-(4-((trifluoromethyl)thio)phenyl)nicotinamide (Stage185.2, 206 mg, 0.5 mmol) and (S)-pyrrolidin-3-ol (52.3 mg, 0.6 mmol)were dissolved in iPrOH (0.5 mL). DIPEA (192 μL, 1.1 mmol) was added andthe RM mixture was heated at 140° C. for 1 h in a pressure safe vial.The vial was cooled to RT and the RM was evaporated to dryness underreduced pressure to give residue that was purified by flashchromatography (RediSep® Silica gel column, n-heptane/EtOAc, from 20% to100% EtOAc). Trituration with n-heptane, filtered and dried afforded thetitle compound as a white crystalline powder. HPLC (Condition 4)t_(R)=5.89 min, UPLC-MS (Condition 3) t_(R)=1.20 min, m/z=464.1 [M+H]⁺.

Stage 185.25-Bromo-6-chloro-N-(4-((trifluoromethyl)thio)phenyl)nicotinamide

DMF (0.12 mL) was added followed by slow addition of SOCl₂ (0.73 mL, 10mmol) to a mixture of 5-bromo-6-chloro-nicotinic acid (473 mg, 2 mmol)in toluene (5 mL), and the RM was then stirred at 80° C. for 1 h. Aftercooling at RT, the toluene was evaporated off under reduce pressure andthe residue was dissolved in THF (0.4 mL). DIPEA (0.7 mL, 4 mmol) wasadded and the solution was cooled to 0° C. under nitrogen.4-trifluoromethylsulfanyl-aniline (438 mg, 2.2 mmol) in THF (1 mL) wasthen added dropwise and the RM was stirred at 0° C. for 2 h. The RM wasdiluted with TBME (50 mL), treated with 1 M HCl and extracted with TBME.The combined extracts were washed with 1 M aq. NaOH and brine, driedover Na₂SO₄ and the solvent was evaporated off under reduced pressureand the product was crystallized from TBME/n-hexane to give the titlecompound as an off-white crystalline powder. HPLC (Condition 4)t_(R)=6.63 min, UPLC-MS (Condition 3) t_(R)=1.33 min, m/z=411.1 [M+H]⁺.

Example 186(R)-6-(3-Hydroxypyrrolidin-1-yl)-5-(pyrimidin-5-yl)-N-(4-((trifluoromethyl)thio)phenyl)nicotinamide

(R)-5-Bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-((trifluoromethyl)thio)phenyl)nicotinamide(Stage 186.1, 92 mg, 0.2 mmol) and pyrimidin-5-ylboronic acid (49.6 mg,0.4 mmol) were dissolved in DME (0.8 mL). A solution of 2 M Na₂CO₃(0.300 mL, 0.6 mmol) was added, the mixture was flushed with argon,heated to 100° C. in a pressure safe vial, then Pd(PPh₃)₂Cl₂ (14 mg,0.02 mmol) was added. The RM was stirred under argon at 80-90° C. for 2h. After cooling at RT, the RM was dissolved in EtOAc and washed withbrine. The organic phase was dried over Na₂SO₄ and the solvent wasevaporated off under reduced pressure to give a residue that waspurified by flash chromatography (RediSep® Silica gel column, (DCM/MeOH98:2)/MeOH, from 0 to 5% MeOH) and treated with Si-Thiol (80 mg) in MeOHto afford the title compound as a beige crystalline powder. HPLC(Condition 4) t_(R)=5.02 min, HPLC Chiral (CHIRALPAK® AD-H, 250×4.6 mm,5 μm, eluent: EtOH/MeOH (50:50), 1 mL/min, UV 220 nm, t_(R)=10.32 min,UPLC-MS (Condition 3) t_(R)=1.00 min, m/z=462.2 [M+H]⁺; ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 1.68-1.79 (m, 1H) 1.78-1.91 (m, 1H) 2.87 (d, J=1.00 Hz,1H) 3.21 (m, J=6.60 Hz, 2H) 3.32-3.42 (m, 1H) 4.14-4.24 (m, 1H) 4.87 (d,J=3.13 Hz, 1H) 7.68 (d, J=8.60 Hz, 2H) 7.90 (d, J=8.60 Hz, 2H) 8.09 (d,J=1.95 Hz, 1H) 8.76-8.80 (m, 1H) 8.88 (s, 2H) 9.18 (s, 1H) 10.26 (s,1H).

Stage 186.1(R)-5-Bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-((trifluoromethyl)thio)phenyl)nicotinamide

DIPEA (73 μL, 0.42 mmol) was added to a solution of5-bromo-6-chloro-N-(4-((trifluoromethyl)thio)phenyl)nicotinamide (Stage185.2, 123 mg, 0.3 mmol) and (R)-pyrrolidin-3-ol (31.4 mg, 0.36 mmol) iniPrOH (300 μL) in a vial, which was sealed and heated at 140° C. for 1h. After cooling at RT, the RM was diluted with EtOAc, washed withbrine, dried over Na₂SO₄ and the solvent evaporated off under reducedpressure to give a residue which was triturated with iPr₂O, filtered anddried to afford the title compound as a white crystalline powder. HPLC(Condition 4) t_(R)=5.9 min, UPLC-MS (Condition 3) t_(R)=1.21 min,m/z=464.1 [M+H]⁺.

Example 187(R)-5′-Fluoro-2-(3-hydroxypyrrolidin-1-yl)-N-(4-((trifluoromethyl)thio)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 151 using(R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-((trifluoromethyl)thio)phenyl)nicotinamide(Stage 186.1) and (5-fluoropyridin-3-yl)boronic acid to afford a yellowcrystals. UPLC-MS (Condition 3) t_(R)=1.08 min, m/z=479.4 [M+H]⁺,m/z=477.1 [M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.68-1.79 (m, 1H)1.78-1.91 (m, 1H) 2.87 (d, J=11.29 Hz, 1H) 3.15-3.30 (m, 2H) 3.35-3.46(m, 1H) 4.16-4.24 (m, 1H) 4.89 (d, J=3.39 Hz, 1H) 7.69 (d, J=8.66 Hz,2H) 7.84 (dt, J=9.72, 2.16 Hz, 1H) 7.89-7.95 (m, 2H) 8.08 (d, J=2.38 Hz,1H) 8.51 (s, 1H) 8.60 (d, J=2.64 Hz, 1H) 8.78 (d, J=2.26 Hz, 1H) 10.29(s, 1H).

Example 188(R)-5′-Cyano-2-(3-hydroxypyrrolidin-1-yl)-N-(4-((trifluoromethyl)thio)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 151 using(R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-((trifluoromethyl)thio)phenyl)nicotinamide(Stage 186.1) and5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile to afforda beige solid. UPLC-MS (Condition 3) t_(R)=1.06 min, m/z=486.1 [M+H]⁺,m/z=484.4 [M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.69-1.79 (m, 1H)1.80-1.92 (m, 1H) 2.85 (d, J=11.29 Hz, 1H) 3.16-3.27 (m, 2H) 3.35-3.43(m, 1H) 4.18-4.25 (m, 1H) 4.90 (d, J=3.64 Hz, 1H) 7.70 (d, J=8.78 Hz,2H) 7.88-7.96 (m, 2H) 8.10 (d, J=2.38 Hz, 1H) 8.41 (t, J=2.07 Hz, 1H)8.80 (d, J=2.38 Hz, 1H) 8.91 (d, J=2.13 Hz, 1H) 9.03 (d, J=1.88 Hz, 1H)10.29 (s, 1H).

Example 189(S)-6-(3-(Hydroxymethyl)pyrrolidin-1-yl)-5-(pyrimidin-5-yl)-N-(4-((trifluoromethyl)thio)phenyl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 185 using(S)-5-bromo-6-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-((trifluoromethyl)thio)phenyl)nicotinamide(Stage 189.1) and pyrimidin-5-ylboronic acid. HPLC (Condition 4)t_(R)=5.13 min, UPLC-MS (Condition 3) t_(R)=1.01 min, m/z=476.3 [M+H]⁺;¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.48-1.64 (m, 1H) 1.84 (m, J=6.30 Hz,1H) 2.15-2.31 (m, 1H) 2.96 (dd, J=10.95, 7.04 Hz, 1H) 3.08-3.42 (m, 5H)4.60 (t, J=5.28 Hz, 1H) 7.68 (d, J=8.60 Hz, 2H) 7.90 (d, J=8.99 Hz, 2H)8.08 (d, J=2.35 Hz, 1H) 8.78 (d, J=2.35 Hz, 1H) 8.88 (s, 2H) 9.17 (s,1H) 10.25 (s, 1H).

Stage 189.1(S)-5-Bromo-6-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-((trifluoromethyl)thio)phenyl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Stage 186.1 using5-bromo-6-chloro-N-(4-((trifluoromethyl)thio)phenyl)nicotinamide (Stage185.2) and (S)-1-pyrrolidin-3-yl-methanol. HPLC (Condition 4) t_(R)=6.17min, UPLC-MS (Condition 3) t_(R)=1.20 min, m/z=476.2/478.2 [M+H]⁺.

Example 190(S)-5′-Fluoro-2-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-((trifluoromethyl)thio)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 185 using(S)-5-bromo-6-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-((trifluoromethyl)thio)phenyl)nicotinamide(Stage 189.1) and3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine. HPLC(Condition 4) t_(R)=5.49 min, UPLC-MS (Condition 3) t_(R)=1.10 min,m/z=493.3 [M+H]⁺; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.45-1.64 (m, 1H)1.76-1.92 (m, 1H) 2.14-2.28 (m, 1H) 2.88-3.02 (m, 1H) 3.11-3.40 (m, 5H)4.60 (t, J=1.00 Hz, 1H) 7.67 (d, J=8.60 Hz, 2H) 7.79-7.85 (m, 1H) 7.90(d, J=8.60 Hz, 2H) 8.06 (d, J=1.96 Hz, 1H) 8.50 (s, 1H) 8.57 (d, J=2.74Hz, 1H) 8.77 (d, J=2.35 Hz, 1H) 10.26 (s, 1H).

Example 191(S)-5′-Cyano-2-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-((trifluoromethyl)thio)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 151 using(S)-5-bromo-6-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-((trifluoromethyl)thio)phenyl)nicotinamide(Stage 189.1) and5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile to afforda yellow solid. UPLC-MS (Condition 3) t_(R)=1.09 min, m/z=500.3 [M+H]⁺,m/z=498.3 [M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.49-1.69 (m, 1H)1.77-1.96 (m, 1H) 2.16-2.30 (m, 1H) 2.97 (dd, J=11.00, 7.09 Hz, 1H)3.10-3.22 (m, 2H) 3.22-3.27 (m, 1H) 3.34-3.45 (m, 2H) 4.60 (br. s, 1H)7.70 (d, J=8.80 Hz, 2H) 7.87-7.99 (m, 2H) 8.09 (d, J=2.45 Hz, 1H) 8.41(t, J=2.08 Hz, 1H) 8.80 (d, J=2.45 Hz, 1H) 8.91 (d, J=2.20 Hz, 1H) 9.02(d, J=1.96 Hz, 1H) 10.27 (s, 1H).

Example 1926-((2-Hydroxyethyl)(methyl)amino)-5-(pyrimidin-5-yl)-N-(4-((trifluoromethyl)thio)phenyl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 185 using5-bromo-6-((2-hydroxyethyl)(methyl)amino)-N-(4-((trifluoromethyl)thio)phenyl)nicotinamide(Stage 192.1) and pyrimidin-5-ylboronic acid to afford an off-whitesolid. HPLC (Condition 4) t_(R)=5.26 min, UPLC-MS (Condition 3)t_(R)=1.00 min, m/z=450.3 [M+H]⁺; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 2.69(s, 3H) 3.40-3.62 (m, 4H) 4.67 (t, J=1.00 Hz, 1H) 7.69 (d, J=8.60 Hz,2H) 7.90 (d, J=1.00 Hz, 2H) 8.14 (d, J=2.30 Hz, 1H) 8.76 (d, J=2.50 Hz,1H) 8.95 (s, 2H) 9.17 (s, 1H) 10.32 (s, 1H).

Stage 192.15-Bromo-6-((2-hydroxyethyl)(methyl)amino)-N-(4-((trifluoromethyl)thio)phenyl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Stage 33.1 using5-bromo-6-chloro-N-(4-((trifluoromethyl)thio)phenyl)nicotinamide (Stage185.2) and 2-methylamino-ethanol to afford an off-white crystallinesolid. HPLC (Condition 4) t_(R)=5.97 min, UPLC-MS (Condition 3)t_(R)=1.18 min, m/z=450.2 [M+H]⁺.

Example 1935′-Fluoro-2-((2-hydroxyethyl)(methyl)amino)-N-(4-((trifluoromethyl)thio)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 185 using5-bromo-6-((2-hydroxyethyl)(methyl)amino)-N-(4-((trifluoromethyl)thio)phenyl)nicotinamide(Stage 192.1) and3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine toafford an off-white foam. HPLC (Condition 4) t_(R)=5.7 min, UPLC-MS(Condition 3) t_(R)=1.10 min, m/z=467.3 [M+H]⁺; ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 2.69 (s, 3H) 3.41-3.63 (m, 4H) 4.66 (t, J=5.28 Hz, 1H)7.68 (d, J=8.99 Hz, 2H) 7.82-7.97 (m, 3H) 8.11 (d, J=2.35 Hz, 1H)8.49-8.63 (m, 2H) 8.74 (d, J=2.35 Hz, 1H) 10.31 (s, 1H).

Example 1945′-Cyano-2-((2-hydroxyethyl)(methyl)amino)-N-(4-((trifluoromethyl)thio)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 151 using5-bromo-6-((2-hydroxyethyl)(methyl)amino)-N-(4-((trifluoromethyl)thio)phenyl)nicotinamide(Stage 192.1) and5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile to afforda yellow solid. UPLC-MS (Condition 3) t_(R)=1.09 min, m/z=474.3 [M+H]⁺,m/z=472.3 [M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 2.70 (s, 3H) 3.42-3.52(m, 2H) 3.52-3.62 (m, 2H) 4.68 (br. s, 1H) 7.70 (d, J=8.56 Hz, 2H)7.88-7.98 (m, 2H) 8.14 (d, J=2.45 Hz, 1H) 8.45 (t, J=2.08 Hz, 1H) 8.77(d, J=2.20 Hz, 1H) 9.00 (dd, J=8.44, 2.08 Hz, 2H) 10.32 (s, 1H).

Example 1956-(Ethyl(2-hydroxyethyl)amino)-5-(pyrimidin-5-yl)-N-(4-((trifluoromethyl)thio)phenyl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 185 using5-bromo-6-(ethyl(2-hydroxyethyl)amino)-N-(4-((trifluoromethyl)thio)phenyl)nicotinamide(Stage 195.1) and pyrimidin-5-ylboronic acid to afford an off-whitefoam. HPLC (Condition 4) t_(R)=5.43 min, UPLC-MS (Condition 3)t_(R)=1.05 min, m/z=464.3 [M+H]⁺; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 0.88(t, J=6.84 Hz, 3H) 3.14 (m, J=7.00, 7.00, 7.00 Hz, 2H) 3.32-3.52 (m, 4H)4.61 (t, J=5.08 Hz, 1H) 7.69 (d, J=8.60 Hz, 2H) 7.90 (d, J=8.60 Hz, 2H)8.10 (d, J=2.35 Hz, 1H) 8.77 (d, J=1.95 Hz, 1H) 9.01 (s, 2H) 9.19 (s,1H) 10.35 (s, 1H).

Stage 195.15-Bromo-6-(ethyl(2-hydroxyethyl)amino)-N-(4-((trifluoromethyl)thio)phenyl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Stage 33.1 using5-bromo-6-chloro-N-(4-((trifluoromethyl)thio)phenyl)nicotinamide (Stage185.2) and 2-ethylamino-ethanol to afford a white crystalline solid.(Reaction Time was 10 h). HPLC (Condition 4) t_(R)=6.33 min, UPLC-MS(Condition 3) t_(R)=1.25 min, m/z=466.2 [M+H]⁺.

Example 1962-(Ethyl(2-hydroxyethyl)amino)-5′-fluoro-N-(4-((trifluoromethyl)thio)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 185 using5-bromo-6-(ethyl(2-hydroxyethyl)amino)-N-(4-((trifluoromethyl)thio)phenyl)nicotinamide(Stage 195.1) and3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine toafford an off-white foam. HPLC (Condition 4) t_(R)=5.89 min, UPLC-MS(Condition 3) t_(R)=1.15 min, m/z=481.3 [M+H]⁺; ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 0.89 (t, J=7.04 Hz, 3H) 3.15 (m, J=6.60 Hz, 2H) 3.32-3.41(m, 2H) 3.47 (m, J=5.90 Hz, 2H) 4.61 (t, J=1.00 Hz, 1H) 7.68 (d, J=8.60Hz, 2H) 7.86-8.00 (m, 3H) 8.07 (d, J=2.35 Hz, 1H) 8.54-8.67 (m, 2H) 8.75(d, J=2.35 Hz, 1H) 10.34 (s, 1H).

Example 1975′-Cyano-2-(ethyl(2-hydroxyethyl)amino)-N-(4-((trifluoromethyl)thio)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 151 using5-bromo-6-(ethyl(2-hydroxyethyl)amino)-N-(4-((trifluoromethyl)thio)phenyl)nicotinamide(Stage 195.1) and5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile to afforda yellow resin. UPLC-MS (Condition 3) t_(R)=1.13 min, m/z=488.3 [M+H]⁺,m/z=486.3 [M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 0.90 (t, J=6.97 Hz,3H) 3.15 (q, J=6.93 Hz, 2H) 3.36-3.40 (m, 2H) 3.44-3.56 (m, 2H) 4.55(br. s, 1H) 7.70 (d, J=8.56 Hz, 2H) 7.85-7.99 (m, 2H) 8.10 (d, J=2.45Hz, 1H) 8.53 (t, J=2.08 Hz, 1H) 8.79 (d, J=2.20 Hz, 1H) 9.04 (dd,J=4.03, 2.08 Hz, 2H) 10.36 (s, 1H).

Example 198(R)—N-(3-Fluoro-4-(trifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5-(pyrimidin-5-yl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 185 using(R)-5-bromo-N-(3-fluoro-4-(trifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide(Stage 198.1) and pyrimidin-5-ylboronic acid to afford a white powder.HPLC (Condition 4) t_(R)=4.88 min, UPLC-MS (Condition 3) t_(R)=0.96 min,m/z=464.2 [M+H]⁺; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.65-1.77 (m, 1H)1.79-1.92 (m, 1H) 2.78-2.94 (m, 1H) 3.15-3.25 (m, 2H) 3.32-3.48 (m, 1H)4.13-4.26 (m, 1H) 4.87 (d, J=3.52 Hz, 1H) 7.46-7.65 (m, 2H) 7.91-8.00(m, 1H) 8.07 (d, J=2.35 Hz, 1H) 8.78 (d, J=2.35 Hz, 1H) 8.87 (s, 2H)9.18 (s, 1H) 10.30 (s, 1H).

Stage 198.1(R)-5-Bromo-N-(3-fluoro-4-(trifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Stage 33.1 using5-bromo-6-chloro-N-(3-fluoro-4-(trifluoromethoxy)phenyl)nicotinamide(Stage 198.2) and (R)-pyrrolidin-3-ol to afford an off-white crystallinesolid. HPLC (Condition 4) t_(R)=5.82 min, UPLC-MS (Condition 3)t_(R)=1.17 min, m/z=464.1 [M+H]⁺.

Stage 198.25-Bromo-6-chloro-N-(3-fluoro-4-(trifluoromethoxy)phenyl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Stage 185.2 using 5-bromo-6-chloro-nicotinic acid and3-fluoro-4-trifluoromethoxy-aniline to afford an off-white crystallinesolid. HPLC (Condition 4) t_(R)=6.43 min, UPLC-MS (Condition 3)t_(R)=1.29 min, m/z=413 [M−H]⁻.

Example 199(R)-5′-Fluoro-N-(3-fluoro-4-(trifluoromethoxy)phenyl)-2-(3-hydroxypyrrolidin-1-yl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 151 using(R)-5-bromo-N-(3-fluoro-4-(trifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide(Stage 198.1) and (5-fluoropyridin-3-yl)boronic acid to afford a yellowwax. UPLC-MS (Condition 3) t_(R)=1.06 min, m/z=481.3 [M+H]⁺, m/z=479.3[M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.70-1.80 (m, 1H) 1.80-1.91 (m,1H) 2.89 (d, J=11.25 Hz, 1H) 3.19-3.29 (m, 2H) 3.35-3.46 (m, 1H) 4.21(br. s, 1H) 4.86 (d, J=3.67 Hz, 1H) 7.55 (m, J=8.56 Hz, 1H) 7.61 (m,J=1.47 Hz, 1H) 7.83 (m, J=1.96 Hz, 1H) 7.98 (dd, J=13.20, 2.20 Hz, 1H)8.07 (d, J=2.20 Hz, 1H) 8.51 (br. s, 1H) 8.60 (d, J=2.69 Hz, 1H) 8.78(d, J=2.20 Hz, 1H) 10.30 (s, 1H).

Example 200(R)-5′-Cyano-N-(3-fluoro-4-(trifluoromethoxy)phenyl)-2-(3-hydroxypyrrolidin-1-yl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 151 using(R)-5-bromo-N-(3-fluoro-4-(trifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide(Stage 198.1) and5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile to afforda yellow solid. UPLC-MS (Condition 3) t_(R)=1.05 min, m/z=488.3 [M+H]⁺,m/z=486.3 [M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.75 (s, 1H) 1.81-1.92(m, 1H) 2.87 (d, J=11.25 Hz, 1H) 3.15-3.27 (m, 2H) 3.33-3.44 (m, 1H)4.21 (br. s, 1H) 4.87 (d, J=3.42 Hz, 1H) 7.51-7.64 (m, 2H) 7.98 (dd,J=13.20, 2.20 Hz, 1H) 8.08 (d, J=2.20 Hz, 1H) 8.40 (t, J=1.96 Hz, 1H)8.79 (d, J=2.20 Hz, 1H) 8.90 (d, J=1.96 Hz, 1H) 9.03 (d, J=1.96 Hz, 1H)10.31 (s, 1H).

Example 201(S)—N-(3-Fluoro-4-(trifluoromethoxy)phenyl)-6-(3-(hydroxymethyl)pyrrolidin-1-yl)-5-(pyrimidin-5-yl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 185 using(S)-5-bromo-N-(3-fluoro-4-(trifluoromethoxy)phenyl)-6-(3-(hydroxymethyl)pyrrolidin-1-yl)nicotinamide(Stage 201.1) and pyrimidin-5-ylboronic acid to afford a white powder.HPLC (Condition 4) t_(R)=4.98 min, UPLC-MS (Condition 3) t_(R)=0.97 min,m/z=478.2 [M+H]⁺; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.50-1.65 (m, 1H) 1.84(m, J=6.60 Hz, 1H) 2.15-2.29 (m, 1H) 2.96 (dd, J=10.75, 6.84 Hz, 1H)3.06-3.42 (m, 5H) 4.60 (t, J=5.28 Hz, 1H) 7.47-7.64 (m, 2H) 7.96 (dd,J=13.10, 2.15 Hz, 1H) 8.06 (d, J=2.35 Hz, 1H) 8.77 (d, J=2.74 Hz, 1H)8.84-8.94 (m, 2H) 9.17 (s, 1H) 10.29 (s, 1H).

Stage 201.1(S)-5-Bromo-N-(3-fluoro-4-(trifluoromethoxy)phenyl)-6-(3-(hydroxymethyl)pyrrolidin-1-yl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Stage 33.1 using5-bromo-6-chloro-N-(3-fluoro-4-(trifluoromethoxy)phenyl)nicotinamide(Stage 198.2) and (S)-1-pyrrolidin-3-yl-methanol to afford an off-whitecrystalline solid. HPLC (Condition 4) t_(R)=5.99 min, UPLC-MS (Condition3) t_(R)=1.18 min, m/z=478.1/480.1 [M+H]⁺.

Example 202(S)-5′-Fluoro-N-(3-fluoro-4-(trifluoromethoxy)phenyl)-2-(3-(hydroxymethyl)pyrrolidin-1-yl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 185 using(S)-5-bromo-N-(3-fluoro-4-(trifluoromethoxy)phenyl)-6-(3-(hydroxymethyl)pyrrolidin-1-yl)nicotinamide(Stage 201.1) and3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine toafford a white powder. HPLC (Condition 4) t_(R)=5.4 min, UPLC-MS(Condition 3) t_(R)=1.07 min, m/z=495.3 [M+H]⁺; ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 1.46-1.64 (m, 1H) 1.73-1.92 (m, 1H) 2.11-2.27 (m, 1H)2.85-3.03 (m, 1H) 3.11-3.39 (m, 5H) 4.60 (t, J=1.00 Hz, 1H) 7.41-7.64(m, 2H) 7.74-7.87 (m, 1H) 7.91-8.00 (m, 1H) 8.04 (d, J=2.35 Hz, 1H) 8.50(s, 1H) 8.58 (d, J=2.74 Hz, 1H) 8.76 (d, J=1.00 Hz, 1H) 10.29 (s, 1H).

Example 203(S)-5′-Cyano-N-(3-fluoro-4-(trifluoromethoxy)phenyl)-2-(3-(hydroxymethyl)pyrrolidin-1-yl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 151 using(S)-5-bromo-N-(3-fluoro-4-(trifluoromethoxy)phenyl)-6-(3-(hydroxymethyl)pyrrolidin-1-yl)nicotinamide(Stage 201.1) and5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile to afforda white powder. UPLC-MS (Condition 3) t_(R)=1.06 min, m/z=502.4 [M+H]⁺,m/z=500.3 [M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.51-1.66 (m, 1H)1.79-1.92 (m, 1H) 2.16-2.30 (m, 1H) 2.96 (dd, J=11.00, 6.85 Hz, 1H)3.10-3.28 (m, 4H) 3.32-3.41 (m, 1H) 4.60 (t, J=5.26 Hz, 1H) 7.50-7.65(m, 2H) 7.98 (dd, J=13.08, 2.32 Hz, 1H) 8.07 (d, J=2.45 Hz, 1H) 8.40 (t,J=2.20 Hz, 1H) 8.79 (d, J=2.45 Hz, 1H) 8.90 (d, J=1.96 Hz, 1H) 9.02 (d,J=1.96 Hz, 1H) 10.30 (s, 1H).

Example 204(R)—N-(3-Chloro-4-(trifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5-(pyrimidin-5-yl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 185 using(R)-5-bromo-N-(3-chloro-4-(trifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide(Stage 204.1) and pyrimidin-5-ylboronic acid to afford a white foam.HPLC (Condition 4) t_(R)=5.17 min, UPLC-MS (Condition 3) t_(R)=1.03 min,m/z=480.1 [M+H]⁺; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.74 (m, J=3.90 Hz,1H) 1.79-1.93 (m, 1H) 2.88 (d, J=11.34 Hz, 1H) 3.21 (m, J=11.10, 4.50Hz, 2H) 3.37 (m, J=7.00 Hz, 1H) 4.11-4.25 (m, 1H) 4.87 (d, J=3.52 Hz,1H) 7.55 (d, J=8.99 Hz, 1H) 7.72-7.86 (m, 1H) 8.10 (dd, J=15.84, 2.54Hz, 2H) 8.74-8.81 (m, 1H) 8.88 (s, 2H) 9.19 (s, 1H) 10.27 (s, 1H).

Stage 204.1(R)-5-Bromo-N-(3-chloro-4-(trifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Stage 33.1 using5-bromo-6-chloro-N-(3-chloro-4-(trifluoromethoxy)phenyl)nicotinamide(Stage 204.2) and (R)-pyrrolidin-3-ol to afford an off-white crystallinesolid. HPLC (Condition 4) t_(R)=6.05 min, UPLC-MS (Condition 3)t_(R)=1.24 min, m/z=480.1/482.1 [M+H]⁺.

Stage 204.25-Bromo-6-chloro-N-(3-chloro-4-(trifluoromethoxy)phenyl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Stage 185.2 using 5-bromo-6-chloro-nicotinic acid and3-chloro-4-(trifluoromethoxy)aniline to afford an off-white crystallinesolid. HPLC (Condition 4) t_(R)=6.72 min, UPLC-MS (Condition 3)t_(R)=1.34 min, m/z=429.0 [M−H]⁻.

Example 205(R)—N-(3-Fluoro-4-((trifluoromethyl)thio)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5-(pyrimidin-5-yl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 185 using(R)-5-bromo-N-(3-fluoro-4-((trifluoromethyl)thio)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide(Stage 205.1) and pyrimidin-5-ylboronic acid to afford a white powder.HPLC (Condition 4) t_(R)=5.22 min, UPLC-MS (Condition 3) t_(R)=1.03 min,m/z=480.2 [M+H]⁺; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.67-1.77 (m, 1H)1.79-1.94 (m, 1H) 2.82-2.94 (m, 1H) 3.22 (m, J=11.10, 4.10 Hz, 2H)3.32-3.45 (m, 1H) 4.14-4.29 (m, 1H) 4.87 (d, J=3.91 Hz, 1H) 7.58-7.80(m, 2H) 7.96 (dd, J=11.73, 1.96 Hz, 1H) 8.08 (d, J=2.35 Hz, 1H) 8.79 (d,J=2.35 Hz, 1H) 8.88 (s, 2H) 9.18 (s, 1H) 10.43 (s, 1H).

Stage 205.1(R)-5-Bromo-N-(3-fluoro-4-((trifluoromethyl)thio)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Stage 33.1 using5-bromo-6-chloro-N-(3-fluoro-4-((trifluoromethyl)thio)phenyl)nicotinamide(Stage 205.2) and (R)-pyrrolidin-3-ol to afford an off-white crystallinesolid. HPLC (Condition 4) t_(R)=6.11 min, UPLC-MS (Condition 3)t_(R)=1.23 min, m/z=480.1 [M+H]⁺.

Stage 205.25-Bromo-6-chloro-N-(3-fluoro-4-((trifluoromethyl)thio)phenyl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Stage 185.2 using 5-bromo-6-chloro-nicotinic acid and3-fluoro-4-trifluoromethylsulfanyl-aniline to afford a white crystallinesolid. HPLC (Condition 4) t_(R)=6.71 min, UPLC-MS (Condition 3)t_(R)=1.34 min, m/z=429 [M−H]⁻.

Example 206(R)-5′-Fluoro-N-(3-fluoro-4-((trifluoromethyl)thio)phenyl)-2-(3-hydroxypyrrolidin-1-yl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 151 using(R)-5-bromo-N-(3-fluoro-4-((trifluoromethyl)thio)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide(Stage 205.1) and (5-fluoropyridin-3-yl)boronic acid to afford a yellowwax which slowly crystallized upon drying. UPLC-MS (Condition 3)t_(R)=1.12 min, m/z=497.3 [M+H]⁺, m/z=495.3 [M−H]⁻; ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 1.67-1.79 (m, 1H) 1.84 (qd, J=8.43, 4.33 Hz, 1H) 2.88 (d,J=11.42 Hz, 1H) 3.18-3.29 (m, 2H) 3.34-3.47 (m, 1H) 4.14-4.27 (m, 1H)4.88 (d, J=3.39 Hz, 1H) 7.67 (dd, J=8.66, 2.01 Hz, 1H) 7.75 (t, J=8.41Hz, 1H) 7.84 (dt, J=9.72, 2.10 Hz, 1H) 7.97 (dd, J=11.73, 2.07 Hz, 1H)8.07 (d, J=2.38 Hz, 1H) 8.48-8.54 (m, 1H) 8.60 (d, J=2.76 Hz, 1H) 8.79(d, J=2.26 Hz, 1H) 10.45 (s, 1H).

Example 207(R)-5′-Cyano-N-(3-fluoro-4-((trifluoromethyl)thio)phenyl)-2-(3-hydroxypyrrolidin-1-yl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 151 using(R)-5-bromo-N-(3-fluoro-4-((trifluoromethyl)thio)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide(Stage 205.1) and5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile to afforda yellow solid. UPLC-MS (Condition 3) t_(R)=1.10 min, m/z=504.3 [M+H]⁺,m/z=502.3 [M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.67-1.78 (m, 1H) 1.83(dd, J=8.72, 4.33 Hz, 1H) 2.84 (d, J=11.29 Hz, 1H) 3.13-3.25 (m, 2H)3.34-3.41 (m, 1H) 4.14-4.24 (m, 1H) 4.87 (d, J=3.51 Hz, 1H) 7.65 (dd,J=8.91, 1.88 Hz, 1H) 7.74 (t, J=8.16 Hz, 1H) 7.95 (dd, J=11.80, 2.13 Hz,1H) 8.07 (d, J=2.38 Hz, 1H) 8.38 (t, J=2.07 Hz, 1H) 8.78 (d, J=2.26 Hz,1H) 8.88 (d, J=2.13 Hz, 1H) 9.01 (d, J=2.01 Hz, 1H) 10.43 (s, 1H).

Example 208(R)-6-(3-Hydroxypyrrolidin-1-yl)-N-(4-(perfluoroethyl)phenyl)-5-(pyrimidin-5-yl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 185 using(R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(perfluoroethyl)phenyl)nicotinamide(Stage 208.1) and pyrimidin-5-ylboronic acid to afford a foam. HPLC(Condition 4) t_(R)=5.11 min, UPLC-MS (Condition 3) t_(R)=1.00 min,m/z=480.2 [M+H]⁺; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.68-1.79 (m, 1H) 1.85(m, J=9.00 Hz, 1H) 2.88 (d, J=11.73 Hz, 1H) 3.14-3.27 (m, 2H) 3.38 (m,J=7.00 Hz, 1H) 4.20 (m, J=2.30 Hz, 1H) 4.87 (d, J=3.52 Hz, 1H) 7.66 (d,J=8.60 Hz, 2H) 7.99 (d, J=8.60 Hz, 2H) 8.10 (d, J=2.35 Hz, 1H) 8.80 (d,J=1.96 Hz, 1H) 8.88 (s, 2H) 9.18 (s, 1H) 10.31 (s, 1H).

Stage 208.1(R)-5-Bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(perfluoroethyl)phenyl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Stage 33.1 using5-bromo-6-chloro-N-(4-(perfluoroethyl)phenyl)nicotinamide (Stage 208.2)and (R)-pyrrolidin-3-ol to afford an off-white crystalline solid. HPLC(Condition 4) t_(R)=5.96 min, UPLC-MS (Condition 3) t_(R)=1.20 min,m/z=480.2 [M+H]⁺.

Stage 208.2 5-Bromo-6-chloro-N-(4-(perfluoroethyl)phenyl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Stage 185.2 using 5-bromo-6-chloro-nicotinic acid and4-pentafluoroethyl-aniline to afford a white crystalline solid. HPLC(Condition 4) t_(R)=6.61 min, UPLC-MS (Condition 3) t_(R)=1.32 min,m/z=429 [M−H]⁻.

Example 209(R)-5′-Fluoro-2-(3-hydroxypyrrolidin-1-yl)-N-(4-(perfluoroethyl)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 151 using(R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(perfluoroethyl)phenyl)nicotinamide(Stage 208.1) and (5-fluoropyridin-3-yl)boronic acid to afford a beigesolid. UPLC-MS (Condition 3) t_(R)=1.10 min, m/z=497.4 [M+H]⁺, m/z=495.3[M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.69-1.79 (m, 1H) 1.85 (m,J=9.05 Hz, 1H) 2.88 (d, J=11.25 Hz, 1H) 3.18-3.29 (m, 2H) 3.35-3.46 (m,1H) 4.16-4.26 (m, 1H) 4.87 (d, J=3.42 Hz, 1H) 7.67 (d, J=8.80 Hz, 2H)7.84 (dt, J=9.66, 2.26 Hz, 1H) 8.00 (d, J=8.80 Hz, 2H) 8.09 (d, J=2.20Hz, 1H) 8.49-8.53 (m, 1H) 8.60 (d, J=2.93 Hz, 1H) 8.80 (d, J=2.20 Hz,1H) 10.33 (s, 1H).

Example 210(R)-5′-Cyano-2-(3-hydroxypyrrolidin-1-yl)-N-(4-(perfluoroethyl)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 151 using(R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(perfluoroethyl)phenyl)nicotinamide(Stage 208.1) and5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile to afforda yellow solid. UPLC-MS (Condition 3) t_(R)=1.08 min, m/z=504.4 [M+H]⁺,m/z=502.3 [M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.69-1.80 (m, 1H)1.80-1.92 (m, 1H) 2.86 (d, J=11.25 Hz, 1H) 3.16-3.28 (m, 2H) 3.39 (m,J=9.29 Hz, 1H) 4.21 (br. s, 1H) 4.89 (d, J=3.18 Hz, 1H) 7.67 (d, J=8.80Hz, 2H) 8.01 (d, J=8.56 Hz, 2H) 8.11 (d, J=2.20 Hz, 1H) 8.38-8.43 (m,1H) 8.81 (d, J=2.20 Hz, 1H) 8.91 (d, J=1.96 Hz, 1H) 9.03 (d, J=1.96 Hz,1H) 10.34 (s, 1H).

Example 211(R)—N-(4-((Difluoromethyl)thio)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5-(pyrimidin-5-yl)nicotinamide

A mixture of(R)-6-(3-hydroxypyrrolidin-1-yl)-5-(pyrimidin-5-yl)nicotinic acid (Stage170.1, 60 mg, 0.21 mmol),O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU, 88 mg, 0.231 mmol) and DIPEA (73.2 μL, 0.419mmol), in DMF (419 μL), was stirred at RT for 10 min.4-Difluoromethylsulfanyl-aniline (60 mg, 0.21 mmol) was added and the RMwas stirred for 2 days. The RM was diluted with EtOAc and washed withbrine. The organic phase was dried over MgSO4 and evaporated to drynessunder reduced pressure. The crude product was purified by preparativeSFC (Column 2-EP, from 20% to 25% in 6 min) to obtain the title compoundas a solid. UPLC-MS (Condition 3), t_(R)=0.86 min, m/z=444.3 [M+H]⁺;¹H-NMR (400 MHz, DMSO-d6), δ ppm (TFA), 1.82 (br. s, 1H) 1.90 (d, J=8.60Hz, 1H) 2.97 (d, J=10.95 Hz, 1H) 3.28 (d, J=7.04 Hz, 2H) 3.35-3.47 (m,1H) 4.26 (br. s, 1H) 7.49-7.63 (m, 2H) 7.79-7.90 (m, 2H) 8.25 (br. s,1H) 8.74 (br. s, 1H) 8.89-8.98 (m, 2H) 9.20-9.28 (m, 1H).

Example 212(R)-5′-Fluoro-2-(3-hydroxypyrrolidin-1-yl)-N-(4-(1,1,2,2-tetrafluoroethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 151 using(R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(1,1,2,2-tetrafluoroethoxy)phenyl)nicotinamide(Stage 212.1) and3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine toafford a solid. UPLC-MS (Condition 3), t_(R)=0.96 min, m/z=495.3; ¹H-NMR(400 MHz, DMSO-d6), δ ppm 1.75 (br. s, 1H) 1.86 (d, J=8.21 Hz, 1H) 2.88(d, J=12.12 Hz, 1H) 3.17-3.29 (m, 3H) 3.35-3.46 (m, 1H) 4.21 (br. s, 1H)4.88 (br. s, 1H) 6.79 (m, 1H) 7.26 (d, J=8.99 Hz, 2H) 7.83 (d, J=9.38Hz, 3H) 8.08 (d, J=2.35 Hz, 1H) 8.51 (s, 1H) 8.60 (d, J=2.74 Hz, 1H)8.76-8.81 (m, 1H) 10.15 (s, 1H).

Stage 212.1(R)-5-Bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(1,1,2,2-tetrafluoroethoxy)phenyl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Stage 33.1 using5-bromo-6-chloro-N-(4-(1,1,2,2-tetrafluoroethoxy)phenyl)nicotinamide(Stage 212.2) and (R)-pyrrolidin-3-ol to afford a solid. UPLC-MS(Condition 3) t_(R)=1.05 min, m/z=478.1 [M+H]⁺.

Stage 212.25-Bromo-6-chloro-N-(4-(1,1,2,2-tetrafluoroethoxy)phenyl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Stage 169.2 using 5-bromo-6-chloro-nicotinic acid and4-(1,1,2,2-tetrafluoroethoxy)aniline to afford a solid. UPLC-MS(Condition 3), t_(R)=1.2 min, m/z=424.9 [M+H]⁺.

Example 213

(R)-2-(3-Hydroxypyrrolidin-1-yl)-6′-methyl-N-(4-(1,1,22-tetrafluoroethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 151 using(R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(1,1,2,2-tetrafluoroethoxy)phenyl)nicotinamide(Stage 212.1) and (6-methylpyridin-3-yl)boronic acid to afford a solid.UPLC-MS (Condition 3), t_(R)=0.87 min, m/z=491.3; ¹H-NMR (400 MHz,DMSO-d6), δ ppm 1.74 (br. s, 1H) 1.83 (d, J=8.60 Hz, 1H) 2.53 (s, 3H)2.88 (d, J=11.73 Hz, 1H) 3.20 (dd, J=11.73, 4.69 Hz, 2H) 3.33-3.45 (m,1H) 4.19 (br. s, 1H) 4.84 (d, J=3.13 Hz, 1H) 6.79 (m, 1H) 7.25 (m,J=8.60 Hz, 2H) 7.34 (d, J=8.21 Hz, 1H) 7.69 (d, J=8.21 Hz, 1H) 7.83 (m,J=8.99 Hz, 2H) 7.99 (s, 1H) 8.49 (s, 1H) 8.75 (d, J=2.35 Hz, 1H) 10.13(s, 1H).

Example 214(R)-6-(3-Hydroxypyrrolidin-1-yl)-5-(pyrimidin-5-yl)-N-(4-((trifluoromethyl)sulfonyl)phenyl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 151 using(R)-5-chloro-6-(3-hydroxypyrrolidin-1-yl)-N-(4-((trifluoromethyl)sulfonyl)phenyl)nicotinamide(Stage 214.1) and pyrimidin-5-ylboronic acid to afford a solid. UPLC-MS(Condition 3), t_(R)=0.92 min, m/z=−492.3; ¹H-NMR (400 MHz, DMSO-d6), δppm 1.74 (br. s, 1H) 1.85 (br. s, 1H) 2.91 (d, J=10.95 Hz, 1H) 3.18-3.26(m, 2H) 3.32-3.45 (m, 1H) 4.22 (br. s, 1H) 4.90 (d, J=3.52 Hz, 1H)8.05-8.16 (m, 3H) 8.16-8.25 (m, 2H) 8.81-8.86 (m, 1H) 8.90 (s, 2H) 9.20(s, 1H) 10.65 (s, 1H).

Stage 214.1(R)-5-Chloro-6-(3-hydroxypyrrolidin-1-yl)-N-(4-((trifluoromethyl)sulfonyl)phenyl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Stage 33.1 using5-bromo-6-chloro-N-(4-((trifluoromethyl)sulfonyl)phenyl)nicotinamide(Stage 214.2) and (R)-pyrrolidin-3-ol to afford a solid. UPLC-MS(Condition 3) t_(R)=1.11 min, m/z=494.1 [M+H]⁺.

Stage 214.25-Bromo-6-chloro-N-(4-((trifluoromethyl)sulfonyl)phenyl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Stage 169.2 using 5-bromo-6-chloro-nicotinic acid and4-trifluoromethanesulfonyl-aniline to afford a solid. UPLC-MS (Condition3) t_(R)=1.23 min, m/z=−441 [M+H]⁺.

Example 215(R)—N-(4-(1,1-Difluoroethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5-(pyrimidin-5-yl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 185 using(R)-5-bromo-N-(4-(1,1-difluoroethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide(Stage 215.1) and pyrimidin-5-ylboronic acid to afford an off-whitefoam. HPLC (Condition 4) t_(R)=4.28 min, UPLC-MS (Condition 3)t_(R)=0.84 min, m/z=442.4 [M+H]⁺; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.74(m, J=4.30 Hz, 1H) 1.81-1.99 (m, 4H) 2.87 (d, J=11.34 Hz, 1H) 3.21 (m,J=11.30, 4.70 Hz, 2H) 3.37 (m, J=7.00 Hz, 1H) 4.15-4.24 (m, 1H) 4.86 (d,J=3.52 Hz, 1H) 7.16 (d, J=8.99 Hz, 2H) 7.74 (d, J=8.60 Hz, 2H) 8.08 (d,J=1.95 Hz, 1H) 8.77 (d, J=1.00 Hz, 1H) 8.87 (s, 2H) 9.18 (s, 1H) 10.06(s, 1H).

Stage 215.1(R)-5-Bromo-N-(4-(1,1-difluoroethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Stage 33.1 using5-bromo-6-chloro-N-(4-(1,1-difluoroethoxy)phenyl)nicotinamide (Stage215.2) and (R)-pyrrolidin-3-ol to afford a white solid. HPLC (Condition4) t_(R)=5.11 min, UPLC-MS (Condition 3) t_(R)=1.02 min, m/z=440.3[M−H]⁻.

Stage 215.25-Bromo-6-chloro-N-(4-(1,1-difluoroethoxy)phenyl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Stage 185.2 using 5-bromo-6-chloro-nicotinic acid and4-(1,1-difluoroethoxy)aniline (Stage 215.3) to afford an off-whitecrystalline solid. HPLC (Condition 5) t_(R)=7.3 min, UPLC-MS (Condition3) t_(R)=1.16 min, m/z=391/393 [M+H]⁺.

Stage 215.3 4-(1,1-Difluoroethoxy)aniline

A solution of 1-(1,1-difluoroethoxy)-4-nitrobenzene (Stage 30.4, 2.95 g,13.94 mmol) in EtOH (100 mL) was hydrogenated (Raney Ni 1.0 g; 26.5 h atRT). The RM was filtered through Hyflo® and the solvent was evaporatedoff under reduced pressure to give the crude title product as a brownoil. HPLC (Condition 5) t_(R)=4.5 min, UPLC-MS (Condition 3) t_(R)=0.74min, m/z=174.1 [M+H]⁺.

Stage 215.4 1-(1,1-Difluoroethoxy)-4-nitrobenzene

4-Nitroacetophenone (2.45 g, 14.54 mmol) and HF-pyridine (10.11 mL, 116mmol) was added to a mixture of XeF2 (4.92 g, 29.1 mmol) and DCM (50 mL)in a plastic vial and the RM was stirred at RT for 20 h. The RM wasadded carefully to a stirred mixture of EtOAc (150 mL) and sat. NaHCO₃(250 mL) and extracted with EtOAc. The combined extracts were washedwith brine (2×100 mL), dried over Na2SO₄ and the solvent was evaporatedoff under reduced pressure to give a crude product which was purified byflash chromatography (Silica gel column, 40 g, n-hexane/EtOAc (95:5)) togive the title product as a yellow oil. HPLC (Condition 4) t_(R)=5.43min, UPLC-MS (Condition 3) t_(R)=1.05 min.

Example 216(R)-6-(3-Hydroxypyrrolidin-1-yl)-5-(pyrimidin-5-yl)-N-(4-(pentafluorosulfanyl)phenyl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 151 using(R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(pentafluorosulfanyl)phenyl)nicotinamide(Stage 216.1) and pyrimidin-5-ylboronic acid to afford a solid. UPLC-MS(Condition 3), t_(R)=0.97 min, m/z=488.2 [M+H]⁺; ¹H-NMR (400 MHz,DMSO-d6), δ ppm 1.74 (m, 1H) 1.84 (m, J=8.99 Hz, 1H) 2.88 (d, J=10.95Hz, 1H) 3.18-3.26 (m, 2H) 3.33-3.43 (m, 1H) 4.20 (br. s, 1H) 4.83-4.97(m, 1H) 7.80-7.88 (m, 2H) 7.91-7.99 (m, 2H) 8.10 (d, J=1.00 Hz, 1H) 8.80(d, J=1.96 Hz, 1H) 8.88 (s, 2H) 9.18 (s, 1H) 10.36 (br. s, 1H).

Stage 216.1(R)-5-Bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(pentafluorosulfanyl)phenyl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Stage 33.1 using5-bromo-6-chloro-N-(4-(pentafluorosulfanyl)phenyl)nicotinamide (Stage216.2) and (R)-pyrrolidin-3-ol to afford a solid. UPLC-MS (Condition 3)t_(R)=1.16 min, m/z=490.1.

Stage 216.25-bromo-6-chloro-N-(4-(pentafluorosulfanyl)phenyl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed infashion to that described in Stage 185.2 using5-Bromo-6-chloro-nicotinic acid and 4-aminophenylsulfur pentafluoride toafford an orange solid. HPLC (Condition 4), t_(R)=6.43 min, UPLC-MS(Condition 3) t_(R)=1.27 min, m/z=435.3/437.2.

Example 217(R)—N-(4-((Chlorodifluoromethyl)thio)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5-(pyrimidin-5-yl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed infashion to that described in Example 185 using(R)-5-bromo-N-(4-((chlorodifluoromethyl)thio)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide(Stage 217.1) and pyrimidin-5-ylboronic acid to afford an off-whitefoam. HPLC (Condition 4) t_(R)=5.27 min, UPLC-MS (Condition 3)t_(R)=1.00 min, m/z=478.3 [M+H]⁺; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm1.66-1.78 (m, 1H) 1.80-1.90 (m, 1H) 2.88 (d, J=11.34 Hz, 1H) 3.21 (m,J=10.90, 4.30 Hz, 2H) 3.32-3.44 (m, 1H) 4.12-4.26 (m, 1H) 4.87 (d,J=3.52 Hz, 1H) 7.67 (d, J=8.60 Hz, 2H) 7.91 (d, J=8.99 Hz, 2H) 8.09 (d,J=2.35 Hz, 1H) 8.79 (d, J=2.35 Hz, 1H) 8.88 (s, 2H) 9.13-9.33 (m, 1H)10.27 (s, 1H).

Stage 217.1(R)-5-Bromo-N-(4-((chlorodifluoromethyl)thio)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed infashion to that described in Stage 33.1 using5-bromo-6-chloro-N-(4-((chlorodifluoromethyl)thio)phenyl)nicotinamide(Stage 217.2) and (R)-pyrrolidin-3-ol to afford an off-white crystallinesolid. HPLC (Condition 4) t_(R)=5.97 min, UPLC-MS (Condition 3)t_(R)=1.19 min, m/z=478.2/480.1 [M+H]⁺.

Stage 217.25-Bromo-6-chloro-N-(4-((chlorodifluoromethyl)thio)phenyl)-nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Stage 11.2 using 5-bromo-6-chloro-nicotinic acid and4-((chloro-difluoromethyl)thio)aniline (Stage 217.3) to afford anoff-white crystalline solid. HPLC (Condition 4) t_(R)=6.78 min, UPLC-MS(Condition 3) t_(R)=1.32 min, m/z=425 [M−H]⁻.

Stage 217.3: 4-((Chlorodifluoromethyl)thio)aniline

To a solution of 4-nitrophenylchlorodifluoromethyl sulfide (prepared asdescribed in DE2845997, 627, 67.5 g, 0.28 mol) in ethanol (270 mL) andwater (68 mL) stirred at 72° C. was added concentrated HCl (3.4 mL, 41.5mmol) and iron powder (203 g, 3.63 mol) in three portions over 10 min.The RM was stirred at 82° C. for 30 min, filtered through Celite®(EtOH), the solvent was evaporated off under reduced pressure to give ayellow oil which was dissolved in DCM and washed with sat. NaHCO₃ andbrine. The organic phase was dried over MgSO4, filtered and the filtratewas evaporated off under reduced pressure to give the crude product as ayellow oil which was distilled (b.p. 88-92° C., 0.9 mmHg) and filteredthrough Celite® to afford the title compound as a pale yellow oil.¹H-NMR (300 MHz, CDCl₃) δ ppm 3.98 (br. s, 2H) 6.67 (dd, 2H) 7.43 (dd,2H).

Example 218(R)—N-(4-((Chlorodifluoromethyl)thio)phenyl)-5′-fluoro-2-(3-hydroxypyrrolidin-1-yl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed infashion to that described in Example 185 using(R)-5-bromo-N-(4-((chlorodifluoromethyl)thio)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide(Stage 217.1) and3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine toafford an off-white foam. HPLC (Condition 4) t_(R)=5.69 min, UPLC-MS(Condition 3) t_(R)=1.09 min, m/z=495.3 [M+H]⁺; ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 1.65-1.77 (m, 1H) 1.79-1.89 (m, 1H) 2.87 (d, J=11.34 Hz,1H) 3.20 (m, J=11.10, 4.50 Hz, 2H) 3.33-3.44 (m, 1H) 4.19 (br. s, 1H)4.86 (d, J=3.13 Hz, 1H) 7.66 (d, J=8.60 Hz, 2H) 7.82 (d, J=9.78 Hz, 1H)7.91 (d, J=8.60 Hz, 2H) 8.06 (d, J=1.00 Hz, 1H) 8.50 (s, 1H) 8.58 (d,J=2.35 Hz, 1H) 8.77 (d, J=1.95 Hz, 1H) 10.27 (s, 1H).

Example 219(R)—N-(4-(tert-Butoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5-(pyrimidin-5-yl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed infashion to that described in Example 170 using(R)-6-(3-hydroxypyrrolidin-1-yl)-5-(pyrimidin-5-yl)nicotinic acid (Stage170.1) and 4-tert-butoxyaniline to afford an off-white foam. HPLC(Condition 4) t_(R)=4.31 min, UPLC-MS (Condition 3) t_(R)=0.84 min,m/z=434.4 [M+H]⁺; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.26 (s, 9H) 1.67-1.77(m, 1H) 1.79-1.91 (m, 1H) 2.88 (d, J=3.91 Hz, 1H) 3.14-3.25 (m, 2H)3.30-3.45 (m, 1H) 4.14-4.24 (m, 1H) 4.86 (d, J=3.52 Hz, 1H) 6.88-7.00(m, 2H) 7.56-7.66 (m, 2H) 8.07 (d, J=2.35 Hz, 1H) 8.76 (d, J=2.35 Hz,1H) 8.87 (d, J=0.78 Hz, 2H) 9.17 (s, 1H) 9.92 (s, 1H).

Example 220(R)-6-(3-Hydroxypyrrolidin-1-yl)-N-(4-(perfluoroethoxy)phenyl)-5-(pyrimidin-5-yl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed infashion to that described in Example 185 using(R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(perfluoroethoxy)phenyl)nicotinamide(Stage 220.1) and pyrimidin-5-ylboronic acid to afford an off-whitesolid. HPLC (Condition 4) t_(R)=5.17 min, UPLC-MS (Condition 3)t_(R)=0.99 min, m/z=496.4 [M+H]⁺; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm1.66-1.77 (m, 1H) 1.79-1.91 (m, 1H) 2.88 (d, J=11.34 Hz, 1H) 3.21 (m,J=11.10, 4.90 Hz, 2H) 3.32-3.44 (m, 1H) 4.20 (d, J=2.35 Hz, 1H) 4.87 (d,J=3.52 Hz, 1H) 7.33 (d, J=8.60 Hz, 2H) 7.85 (d, J=9.38 Hz, 2H) 8.08 (d,J=2.35 Hz, 1H) 8.78 (d, J=2.35 Hz, 1H) 8.88 (s, 2H) 9.13-9.34 (m, 1H)10.16 (s, 1H).

Stage 220.1(R)-5-Bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(perfluoroethoxy)phenyl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed infashion to that described in Stage 33.1 using5-bromo-6-chloro-N-(4-(perfluoroethoxy)phenyl)nicotinamide (Stage 220.2)and (R)-pyrrolidin-3-ol to afford an off-white crystalline solid. HPLC(Condition 4) t_(R)=6.01 min, UPLC-MS (Condition 3) t_(R)=1.17 min,m/z=496.2 [M+H]⁺.

Stage 220.2 5-Bromo-6-chloro-N-(4-(perfluoroethoxy)phenyl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed infashion to that described in Stage 169.2 using5-bromo-6-chloro-nicotinic acid and 4-(perfluoroethoxy)aniline to affordan off-white crystalline solid. HPLC (Condition 4) t_(R)=6.73 min,UPLC-MS (Condition 3) t_(R)=1.30 min, m/z=443.1 [M−H]⁻.

Example 221(R)-5′-Fluoro-2-(3-hydroxypyrrolidin-1-yl)-N-(4-(perfluoroethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 185 using(R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(perfluoroethoxy)phenyl)nicotinamide(Stage 220.1) and3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine toafford an off-white foam. HPLC (Condition 4) t_(R)=5.58 min, UPLC-MS(Condition 3) t_(R)=1.07 min, m/z=513.4 [M+H]⁺; ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 1.67-1.76 (m, 1H) 1.78-1.89 (m, 1H) 2.86 (d, J=11.34 Hz,1H) 3.13-3.26 (m, 2H) 3.33-3.43 (m, 1H) 4.19 (br. s, 1H) 4.85 (d, J=3.13Hz, 1H) 7.33 (d, J=8.99 Hz, 2H) 7.76-7.90 (m, 3H) 8.03-8.09 (m, 1H) 8.49(s, 1H) 8.58 (d, J=2.74 Hz, 1H) 8.72-8.82 (m, 1H) 8.99-9.00 (m, OH)10.16 (s, 1H).

Example 2225′-Fluoro-2-((R)-3-hydroxypyrrolidin-1-yl)-N-(4-((trifluoromethyl)sulfinyl)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 185 using5-bromo-6-((R)-3-hydroxypyrrolidin-1-yl)-N-(4-((trifluoromethyl)sulfinyl)phenyl)nicotinamide(Stage 222.1) and3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine toafford an off-white foam. HPLC (Condition 4) t_(R)=4.46 min, UPLC-MS(Condition 3) t_(R)=0.87 min, m/z=495.3 [M+H]⁺; ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 1.65-1.78 (m, 1H) 1.79-1.88 (m, 1H) 2.88 (d, J=1.00 Hz,1H) 3.22 (m, J=4.70 Hz, 2H) 3.34-3.44 (m, 1H) 4.14-4.23 (m, 1H) 4.86 (d,J=3.52 Hz, 1H) 7.86 (d, J=8.99 Hz, 3H) 8.01-8.14 (m, 3H) 8.50 (s, 1H)8.59 (d, J=2.74 Hz, 1H) 8.79 (d, J=2.35 Hz, 1H) 10.40 (s, 1H).

Stage 222.15-Bromo-6-((R)-3-hydroxypyrrolidin-1-yl)-N-(4-((trifluoromethyl)sulfinyl)phenyl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Stage 33.1 using5-bromo-6-chloro-N-(4-((trifluoromethyl)sulfinyl)phenyl)nicotinamide(Stage 222.2) and (R)-pyrrolidin-3-ol to afford an amorphous off-whitesolid. HPLC (Condition 4) t_(R)=4.83 min, UPLC-MS (Condition 3)t_(R)=0.95 min, m/z=478.2 [M+H]⁺.

Stage 222.25-Bromo-6-chloro-N-(4-((trifluoromethyl)sulfinyl)phenyl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Stage 169.2 using 5-bromo-6-chloro-nicotinic acid and4-(trifluoromethylsulfinyl)aniline To afford an off-white crystallinesolid. HPLC (Condition 4) t_(R)=5.59 min, UPLC-MS (Condition 3)t_(R)=1.10 min, m/z=425 [M−H]⁻.

Example 223(R)-6-(3-Amino-3-(trifluoromethyl)pyrrolidin-1-yl)-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

6-Chloro-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 223.1, 150 mg, 0.380 mmol) was suspended in iPrOH (0.6 mL).tert-Butyl[3-(trifluoromethylpyrrolidine-3-yl)]carbamate (193 mg, 0.760mmol) and DIPEA (0.265 mL, 1.520 mmol) were added at RT. The pink/redsuspension was stirred at 140° C. for 22 h. The orange reaction solutionwas diluted with EtOAc (50 mL) then washed with a 2 N citric acidsolution (20 mL) and water (3×20 mL). Aq. phases were back-extractedwith EtOAc (40 mL). The combined organic phases were dried over Na₂SO₄,filtered, and the solvent was evaporated off under reduced pressure togive a crude product that was purified by flash chromatography (RediSep®Silica gel column, 40 g, DCM/EtOAc 7:3). The resulting intermediate (135mg, 0.22 mmol) was suspended in DCM (2 mL). TFA (0.679 mL, 8.82 mmol)was added at RT and the resulting light yellow solution was stirred for2 h at RT. The RM was diluted with EtOAc (50 mL), washed with an aq.sat. solution of NaHCO₃ (2×20 mL) and water (2×20 mL). Aq. phases wereback-extracted with EtOAc (40 mL). The combined organic phases weredried over Na₂SO₄, filtered, and the solvent was evaporated off underreduced pressure to give a crude product that was suspended in MeCN (2mL). The white suspension was stirred for 30 min at RT then filtered.The solid was washed with MeCN (2 mL) and dried under reduced pressureto give the title product as a white solid. HPLC (Condition 10)t_(R)=5.748 min, UPLC-MS (Condition 3) t_(R)=1.03 min, m/z=513.1 [M+H]⁺;¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.75-1.85 (m, 1H) 1.96-2.08 (m, 1H)2.24-2.35 (m, 2H) 3.13-3.26 (m, 2H) 3.36-3.52 (m, 2H) 7.36 (d, J=8.99Hz, 2H) 7.86 (d, J=8.99 Hz, 2H) 8.14 (d, J=2.35 Hz, 1H) 8.81 (d, J=2.35Hz, 1H) 8.92 (s, 2H) 9.22 (s, 1H) 10.22 (s, 1H).

Stage 223.16-Chloro-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

A mixture of 6-chloro-5-iodo-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 223.2, 5.7 g, 12.75 mmol), pyrimidine-5-boronic acid (2.5 g,19.77 mmol), PdCl₂(dppf)-(CH₂Cl₂) (0.625 g, 0.765 mmol), Na₂CO₃ (19.13mL, 38.3 mmol) and DME (100 mL) was stirred at 80° C. for 2.5 h underargon atmosphere. The RM was filtered through Hyflo®, diluted with EtOAc(100 mL), washed with a sat. aq. solution of NaHCO₃ and with brine,dried over Na₂SO₄ and the solvent was evaporated off under reducedpressure to give the crude product which was purified by flashchromatography (Biotage Silica gel column, 120 g, n-hexane/EtOAc from20% to 60% EtOAc) to give the title compound product as a pinkcrystalline solid. UPLC-MS (Condition 3) t_(R)=1.01 min, 393.2 [M−H]⁻;1H-NMR (400 MHz, DMSO-d₆) δ ppm 7.42 (d, J=8.99 Hz, 2H) 7.88 (d, J=9.38Hz, 2H) 8.56 (d, J=2.35 Hz, 1H) 9.03 (d, J=2.35 Hz, 1H) 9.10 (s, 2H)9.32 (s, 1H) 10.69 (s, 1H).

Stage 223.2 6-Chloro-5-iodo-N-(4-(trifluoromethoxy)phenyl)nicotinamide

DMF (0.014 mL, 0.176 mmol) and oxalyl chloride (2.316 mL, 26.5 mmol)were added to a solution of 6-chloro-5-iodonicotinic acid (5 g, 17.64mmol) in DCM (80 mL) and the RM was stirred for 2 h at RT under anitrogen atmosphere. The solvent was evaporated off under reducedpressure and the residue was dissolved in THF (60 mL). DIPEA (9.24 mL,52.9 mmol) was added and the mixture was cooled down to 5° C., treateddropwise with a solution of 4-(trifluoro methoxy)aniline (2.62 mL, 19.40mmol) in DCM (20 mL) and stirred at 5° C. for 30 min and at RT for 1 h.The solvent was off under reduced pressure and the residue was treatedwith aq. 10% citric acid (70 mL) and extracted with EtOAc. The combinedextracts were washed with sat. aq. Na₂CO₃ and brine, dried over Na₂SO₄and the solvent was evaporated off under reduced pressure to give thecrude product was suspended in n-hexane, and filtered to afford thetitle compound as a beige solid. UPLC-MS (Condition 3) t_(R)=1.22 min,440.9/442.9 [M−H]⁻.

Example 2246-(3,3-Difluoropyrrolidin-1-yl)-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

6-Chloro-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 223.1, 100 mg, 0.253 mmol) was suspended in iPrOH (0.5 mL).3,3-Difluoropyrrolidine hydrochloride (72.7 mg, 0.507 mmol) and DIPEA(0.177 mL, 1.013 mmol) were added at RT. The light brown solution wasstirred at 140° C. for 23 h. The RM was diluted with EtOAc (50 mL) andwashed with a 2 N citric acid solution (20 mL) and water (3×20 mL). Thecombined aq. phases were extracted with EtOAc and the combined extractswere dried over Na₂SO₄, filtered, and the solvent was evaporated offunder reduced pressure to give the crude material that was purified byflash chromatography (RediSep® Silica gel column, 24 g, DCM/EtOAc 7:3).The resulting product was dissolved in MeOH (2 mL). The resulting whitesuspension was stirred at RT for 15 min then filtered. The solid waswashed with MeOH (5 mL) and dried to afford the title product as a whitesolid. HPLC (Condition 10) t_(R)=7.017 min, UPLC-MS (Condition 3)t_(R)=1.09 min, m/z=466.1 [M+H]⁺; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 2.39(spt, J=7.04 Hz, 2H) 3.37 (t, J=7.23 Hz, 2H) 3.62 (t, J=13.10 Hz, 2H)7.37 (d, J=8.99 Hz, 2H) 7.82-7.89 (m, 2H) 8.15-8.19 (m, 1H) 8.82-8.85(m, 1H) 8.94 (d, J=0.78 Hz, 2H) 9.23 (s, 1H) 10.27 (s, 1H).

Example 2256-((3S,4S)-3-(Dimethylamino)-4-hydroxypyrrolidin-1-yl)-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

6-Chloro-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 223.1, 60 mg, 0.149 mmol) and DIPEA (0.182 mL, 1.043 mmol) wereadded to a vial containing iPrOH (1 mL).(3S,4S)-4-(Dimethylamino)pyrrolidin-3-ol (50 mg, 0.246 mmol) was added.The mixture was stirred at 110° C. for 16 h. The RM was treated withsat. aq. Na₂CO₃ (20 mL) and was extracted with EtOAc. The combinedextracts were washed with brine (10 mL), dried over Na₂SO₄, filtered andthe filtrate was evaporated off under reduced pressure to give a crudeproduct that was purified by preparative SFC (Column DEAP, from 13% to18% in 6 min) to afford the title product as a white solid. HPLC(Condition 10) t_(R)=5.62 min, UPLC-MS (Condition 3) t_(R)=0.73 min,m/z=489.1 [M+H]⁺; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 2.15 (s, 6H) 2.52-2.59(m, 1H) 2.87 (dd, J=10.95, 5.08 Hz, 1H) 3.19 (dd, J=11.34, 5.90 Hz, 1H)3.28 (m, J=11.30, 6.30 Hz, 1H) 3.45 (dd, J=11.34, 6.65 Hz, 1H) 4.08(quin, J=5.08 Hz, 1H) 5.09 (d, J=5.08 Hz, 1H) 7.36 (d, J=8.60 Hz, 2H)7.85 (m, J=9.00 Hz, 2H) 8.11 (d, J=2.35 Hz, 1H) 8.80 (d, J=2.35 Hz, 1H)8.90 (s, 2H) 9.20 (s, 1H) 10.19 (s, 1H).

Example 2266-(1-Amino-3-azabicyclo[3.1.0]hexan-3-yl)-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

6-Chloro-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 223.1, 100 mg, 0.253 mmol) was dissolved in iPrOH (0.25 mL).DIPEA (97 μL, 2.2 mmol) was added and the RM mixture was stirred at 140°C. for 18 h in a pressure safe vial. The RM was cooled to RT, dilutedwith EtOAc and washed with brine. The organic layer was dried overNa₂SO₄, filtered and the filtrate was evaporated off under reducedpressure to give the intermediate which was dissolved in DCM (1.2 mL),cooled to 0° C. and treated with TFA (0.6 mL). The reaction mixture wasstirred at RT for 3 h then neutralized with NaHCO₃/water and extractedwith EtOAc. The combined extracts were dried over Na₂SO₄, filtered andthe filtrate was evaporated off under reduced pressure to give the crudeproduct that was purified by preparative SFC to afford the titlecompound as an off-white amorphous powder. HPLC (Condition 4) t_(R)=4.18min, UPLC-MS (Condition 3) t_(R)=0.75 min, m/z=457.1 [M+H]⁺; ¹H-NMR (400MHz, DMSO-d₆) δ ppm 0.30 (t, J=4.50 Hz, 1H) 0.76 (dd, J=8.21, 4.69 Hz,1H) 1.26-1.37 (m, 1H) 3.10 (d, J=10.17 Hz, 1H) 3.31-3.50 (m, 5H) 7.33(d, J=8.99 Hz, 2H) 7.76-7.88 (m, 2H) 8.05 (d, J=2.35 Hz, 1H) 8.75 (d,J=0.78 Hz, 1H) 8.88 (s, 2H) 9.20 (s, 1H) 10.17 (s, 1H).

Example 227-233

The following examples were prepared in an analogous fashion to thatdescribed in the Example using the Stage and starting material asindicated.

Example/Stage and starting material Ex. Structure/Name Analytics 227

226/223.1 and tert-butyl (1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-ylcarbamate HPLC (Condition 4) t_(R) = 4.19min, UPLC-MS (Condition 3) t_(R) = 0.75 min, m/z = 457.1 [M + H]⁺;¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.60 (br. s, 2 H) 2.03 (br. s, 1 H)3.10-3.43 (m, 6 H) 7.33 (d, J = 8.99 Hz, 2 H) 7.77-7.87 (m, 2 H) 8.05(d, J = 1.56 Hz, 1 H) 8.72-8.79 (m, 1 H) 8.88 (s, 2 H) 9.20 (s, 1 H)10.17 (s, 1 H). 228

224/223.1 and 1,4,5,6-tetrahydropyrrolo[3,4- c]pyrazole HPLC (Condition10) t_(R) = 5.92 min, UPLC-MS (Condition 3) t_(R) = 0.93 min, m/z = 468[M + H]⁺; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 4.33 (d, J = 15.25 Hz, 4 H)7.36 (d, J = 8.99 Hz, 2 H) 7.49 (br. s, 1 H) 7.86 (d, J = 8.99 Hz, 2 H)8.09 (d, J = 2.35 Hz, 1 H) 8.88 (d, J = 1.95 Hz, 1 H) 8.99 (s, 2 H) 9.26(s, 1 H) 10.23 (s, 1 H) 12.67 (br. s, 1 H). 229

226/223.1 and tert-butyl 4,7- diazaspiro[2.5]octane-4-carboxylate HPLC(Condition 4) t_(R) = 4.19 min, UPLC-MS (Condition 3) t_(R) = 0.77 min,m/z = 471.1 [M + H]⁺; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 0.27-0.38 (m, 2 H)0.42-0.53 (m, 2 H) 2.75 (br. s, 2 H) 3.04 (s, 2 H) 3.08-3.16 (m, 2 H)3.30 (br. s, 1 H) 7.36 (d, J = 8.99 Hz, 2 H) 7.79- 7.91 (m, 2 H) 8.20(d, J = 2.35 Hz, 1 H) 8.80 (d, J = 2.35 Hz, 1 H) 9.08 (d, J = 0.78 Hz, 2H) 9.20 (d, J = 0.78 Hz, 1 H) 10.34 (s, 1 H). 230

224/223.1 and 2-hydroxymethylmorpholine HPLC (Condition 10) t_(R) = 5.96min, UPLC-MS (Condition 3) t_(R) = 0.89 min, m/z = 476 [M + H]⁺; ¹H-NMR(400 MHz, DMSO-d₆) δ ppm 2.57- 2.70 (m, 1 H) 2.80-2.92 (m, 1 H)3.19-3.28 (m, 1 H) 3.31-3.49 (m, 3 H) 3.56 (d, J = 12.90 Hz, 1 H) 3.75(d, J = 11.34 Hz, 1 H) 4.66 (t, J = 5.28 Hz, 1 H) 7.38 (d, J = 8.99 Hz,2 H) 7.83-7.89 (m, 2 H) 8.21-8.25 (m, 1 H) 8.84 (dd, J = 2.30, 0.80 Hz,1 H) 9.11 (d, J = 0.78 Hz, 2 H) 9.21 (d, J = 0.78 Hz, 1 H) 10.35 (s, 1H). 231

226/223.1 and tert-butyl azetidin-3-ylcarbamate HPLC (Condition 10)t_(R) = 5.49 min, UPLC-MS (Condition 3) t_(R) = 0.73 min, m/z = 431.1[M + H]⁺; ¹H-NMR (400 MHz, DMSO-d₆ + D₂O) δ ppm 1.98 (br. s, 2 H) 3.37(dd, J = 8.99, 5.47 Hz, 2 H) 3.58- 3.67 (m, 1 H) 3.85 (t, J = 8.02 Hz, 2H) 7.36 (d, J = 8.99 Hz, 2 H) 7.85 (m, J = 9.00 Hz, 2 H) 8.08 (d, J =2.35 Hz, 1 H) 8.79 (d, J = 2.35 Hz, 1 H) 8.90 (s, 2 H) 9.22 (s, 1 H)10.19 (s, 1 H). 232

225/223.1 and N,N-dimethylazetidin-3-amine HPLC (Condition 10) t_(R) =5.72 min, UPLC-MS (Condition 3) t_(R) = 0.74 min, m/z = 459.2 [M + H]⁺;¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.99 (s, 6 H) 3.00 (quin, J = 5.86 Hz, 1H) 3.54 (dd, J = 8.99, 5.08 Hz, 2 H) 3.71-3.78 (m, 2 H) 7.36 (d, J =8.99 Hz, 2 H) 7.85 (m, J = 9.00 Hz, 2 H) 8.11 (d, J = 2.35 Hz, 1 H) 8.80(d, J = 2.30 Hz, 1 H) 8.93 (d, J = 0.78 Hz, 2 H) 9.22 (d, J = 0.78 Hz, 1H) 10.23 (s, 1 H). 233

224/223.1 and 1,4-oxazepane HPLC (Condition 10) t_(R) = 6.39 min,UPLC-MS (Condition 3) t_(R) = 1.01 min, m/z = 460.1 [M + H]⁺; ¹H-NMR(400 MHz, DMSO-d₆) δ ppm 1.74 (quin, J = 5.57 Hz, 2 H) 3.36-3.46 (m, 4H) 3.56 (t, J = 5.28 Hz, 2 H) 3.66 (t, J = 4.30 Hz, 2 H) 7.37 (d, J =8.99 Hz, 2 H) 7.81-7.90 (m, 2 H) 8.14 (d, J = 2.35 Hz, 1 H) 8.79 (d, J =2.35 Hz, 1 H) 8.96 (s, 2H) 9.20 (s, 1 H) 10.25 (s, 1 H).

Example 234(R)-2-(3-Hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-5′-(trifluoromethyl)-[3,3′-bipyridine]-5-carboxamide

A mixture of(R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 35.1, 112 mg, 0.25 mmol),(5-(trifluoromethyl)pyridin-3-yl)boronic acid (71.6 mg, 0.375 mmol) andCs₂CO₃ (163 mg, 0.5 mmol) in degassed dioxane (3 mL) in a MW vial wasevacuated/purged with argon. PdCl₂(dppf)-(CH₂Cl₂) (20.42 mg, 0.025 mmol)was added and the vial sealed. Water (0.6 mL) was added and the RM wasstirred at 65° C. for 3.5 h. The solvent was evaporated off underreduced pressure to give a residue that was treated with water andextracted with EtOAc. The combined extracts were washed with water andbrine, dried over MgSO₄/charcoal, filtered and the filtrate wasevaporated off under reduced pressure to give a residue that waspurified by flash chromatography (Silica gel column, 25 g, EtOAc).Palladium was removed using a SPE PL-Thiol MP cartridge(StratoSpheres™). The residue was dissolved in EtOAc and n-heptane wasadded. The solution was concentrated under reduced and the resultingsuspension was stirred and filtered. The solid was washed with n-hexanethen dried under HV at 45° C. to afford the title product as anamorphous white powder. UPLC-MS (Condition 3), t_(R)=1.09 min, m/z=513.1[M+H]⁺; ¹H-NMR (600 MHz, DMSO-d₆) δ ppm 1.69-1.78 (m, 1H) 1.80-1.89 (m,1H) 2.85 (d, J=10.92 Hz, 1H) 3.13-3.26 (m, 2H) 3.27-3.40 (m, 1H) 4.20(br. s, 1H) 4.88 (br. s, 1H) 7.36 (d, J=8.66 Hz, 2H) 7.85 (d, J=8.85 Hz,2H) 8.11 (s, 1H) 8.27 (br. s, 1H) 8.79 (s, 1H) 8.93 (s, 1H) 8.99 (s, 1H)10.19 (s, 1H).

Example 2352-(cis-3,4-Dihydroxypyrrolidin-1-yl)-5′-fluoro-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 71 using5-bromo-6-((3S,4R)-3,4-dihydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 71.1) and 5-fluoropyridin-3-ylboronic acid to afford a brownsolid. UPLC-MS (Condition 3) t_(R)=0.92 min, m/z=479.1 [M+H]⁺, m/z=477.2[M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 3.05 (dd, J=10.88, 4.28 Hz, 2H)3.25 (dd, J=10.64, 5.01 Hz, 2H) 3.92-4.02 (m, 2H) 4.90 (d, J=3.79 Hz,2H) 7.35 (d, J=8.44 Hz, 2H) 7.80-7.84 (m, 1H) 7.84-7.90 (m, 2H) 8.08 (d,J=2.32 Hz, 1H) 8.47-8.53 (m, 1H) 8.61 (d, J=2.69 Hz, 1H) 8.77 (d, J=2.32Hz, 1H) 10.19 (s, 1H).

Example 2362-((3S,4S)-3-(Dimethylamino)-4-hydroxypyrrolidin-1-yl)-5′-fluoro-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

2-Chloro-5′-fluoro-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide(Stage 236.1, 60 mg, 0.137 mmol) and DIPEA (0.167 mL, 0.959 mmol) wereadded to a vial containing iPrOH (1 mL).(3S,4S)-4-(dimethylamino)pyrrolidin-3-ol (50 mg, 0.246 mmol) was added.The mixture was stirred at 110° C. for 16 h. The solvent was evaporatedoff under reduced pressure and the residue was purified by preparativeSFC (Column DEAP, from 15% to 20% in 6 min) to afford the title productas a beige foam. HPLC (Condition 10) t_(R)=5.93 min, UPLC-MS (Condition3) t_(R)=0.81 min, m/z=506.1 [M+H]⁺; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm2.14 (s, 6H) 2.52-2.58 (m, 1H) 2.88 (dd, J=11.14, 5.28 Hz, 1H) 3.21 (dd,J=11.34, 5.86 Hz, 1H) 3.28 (dd, J=10.56, 5.86 Hz, 1H) 3.44 (dd, J=11.34,7.00 Hz, 1H) 4.07 (quin, J=5.28 Hz, 1H) 5.07 (d, J=5.08 Hz, 1H) 7.35 (d,J=9.38 Hz, 2H) 7.85 (d, J=9.38 Hz, 3H) 8.09 (d, J=2.35 Hz, 1H) 8.52 (s,1H) 8.61 (d, J=2.35 Hz, 1H) 8.78 (d, J=2.35 Hz, 1H) 10.19 (s, 1H).

Stage 236.12-Chloro-5′-fluoro-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Stage 223.1 using6-chloro-5-iodo-N-(4-(trifluoromethoxy)phenyl)nicotinamide and3-fluoropyridine-5-boronic acid pinacol ester. The crude product wasdissolved in DCM (20 mL) and treated with n-hexane. The resulting solidwas filtered off, washed with n-hexane and dried to afford the titleproduct as a beige solid. UPLC-MS (Condition 3) t_(R)=1.13 min, m/z=412[M+H]⁺.

Example 2372-(3-(Aminomethyl)-4-hydroxypyrrolidin-1-yl)-5′-fluoro-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

4-Boc-aminomethyl-1-N-Boc-pyrrolidine (71.5 mg, 0.226 mmol) wasdissolved in DCM (1 mL) and treated with TFA (0.095 mL, 1.233 mmol). Themixture was stirred 20 h at RT. The solvent was evaporated under reducedpressure and the residue was dissolved in iPrOH (1 mL).2-Chloro-5′-fluoro-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide(Stage 236.1, 90 mg, 0.205 mmol) and DIPEA (0.359 mL, 2.055 mmol) wereadded. The RM was then stirred 80° C. for 48 h. The RM was treated withsat. aq. Na₂CO₃ (20 mL) and was extracted with EtOAc. The combinedextracts were washed with brine (10 mL), dried over Na₂SO₄, filtered andthe filtrate was evaporated off under reduced pressure to give a. crudeproduct that was purified by preparative HPLC (Condition 14). TFA wasremoved using a PL-HCO₃ cartridge (StratoSpheres™) to afford the titleproduct as a beige solid. HPLC (Condition 10) t_(R)=5.617 min, UPLC-MS(Condition 3) t_(R)=0.79 min, m/z=492.1 [M+H]⁺; ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 2.01-2.14 (m, 1H) 2.51-2.58 (m, 1H) 2.72 (dd, J=12.90,6.30 Hz, 1H) 2.83 (dd, J=11.30, 4.30 Hz, 1H) 3.11-3.24 (m, 2H) 3.51-3.59(m, 1H) 3.95 (q, J=5.08 Hz, 1H) 7.36 (d, J=8.99 Hz, 2H) 7.85 (m, J=9.40Hz, 3H) 8.10 (d, J=2.35 Hz, 1H) 8.52 (s, 1H) 8.61 (d, J=2.74 Hz, 1H)8.78 (dd, J=2.35, 1.17 Hz, 1H) 10.19 (s, 1H).

Example 238 2-(3-Aminoazetidin-1-yl)-5′-fluoro-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

2-Chloro-5′-fluoro-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide(Stage 236.1, 70 mg, 0.160 mmol) and DIPEA (0.070 mL, 0.4 mmol) wereadded to a vial with iPrOH (1 mL). tert-Butyl azetidin-3-ylcarbamate(70.2 mg, 0.4 mmol) was added. The mixture was stirred at 110° C. for 5h. tert-Butyl azetidin-3-ylcarbamate (35 mg) was added and the RM wasstirred for further 5 h at 110° C. The RM was treated with citric acid10% (10 mL) and extracted with EtOAc. The combined extracts were washedwith an aq. sat. solution of NaHCO₃ (10 mL) and with brine (2×10 mL),dried over Na₂SO₄, filtered and the filtrate was evaporated off underreduced pressure to afford the crude product that was purified by flashchromatography (Silica gel column, 4 g, DCM/EtOH from 99:1 to 9:1). Theresulting intermediate (33 mg, 0.054 mmol) was dissolved in DCM (1 mL).TFA (0.167 mL, 2.170 mmol) was added and the RM was stirred for 2 h atRT. The RM was treated sat. aq. Na₂CO₃ (20 mL) and extracted with DCM.The combined extracts were washed with brine (20 mL), dried over Na₂SO₄,filtered and the filtrate was evaporated off under reduced pressure togive a crude product that was purified by preparative HPLC. Fractionscontaining product were combined and treated with 100 mg Na₂CO₃ and theMeCN was removed. The aq. residue was extracted with DCM (3×10 mL) andthe combined extracts were dried over Na₂SO₄, filtered and the filtratewas evaporated off under reduced pressure to afford the title product asa white foam. HPLC (Condition 10) t_(R)=5.77 min, UPLC-MS (Condition 3)t_(R)=0.81 min, m/z=448.2 [M+H]⁺; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 3.36(dd, J=8.60, 5.47 Hz, 2H) 3.56-3.68 (m, 1H) 3.84 (t, J=7.82 Hz, 2H) 7.35(d, J=8.99 Hz, 2H) 7.85 (m, J=9.40 Hz, 3H) 8.06 (d, J=2.35 Hz, 1H) 8.53(s, 1H) 8.62 (d, J=2.74 Hz, 1H) 8.78 (d, J=2.35 Hz, 1H) 10.20 (s, 1H).

Example 2392-(3-(Dimethylamino)azetidin-1-yl)-5′-fluoro-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 236 using2-chloro-5′-fluoro-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide(Stage 236.1) and N,N-dimethylazetidin-3-amine. The crude product waspurified by preparative HPLC (Condition 14). Fractions containingproduct were combined, treated with sat. aq. Na₂CO₃ and the MeCN wasremoved. The aq. phase was extracted with DCM and the combined organiclayers were dried over Na₂SO₄, filtered and the filtrate was evaporatedoff under reduced pressure to afford the title product as whitecrystals. HPLC (Condition 10) t_(R)=6.01 min, UPLC-MS (Condition 3)t_(R)=0.82 min, m/z=476.1 [M+H]⁺; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.99(s, 6H) 2.95-3.04 (m, 1H) 3.53 (dd, J=9.19, 5.28 Hz, 2H) 3.69-3.77 (m,2H) 7.36 (d, J=8.99 Hz, 2H) 7.87 (d, J=8.99 Hz, 3H) 8.08 (d, J=2.35 Hz,1H) 8.54-8.57 (m, 1H) 8.63 (d, J=2.74 Hz, 1H) 8.79 (d, J=2.35 Hz, 1H)10.23 (s, 1H).

Example 240(R)-4′-Cyano-2-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

(R)-5-Bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 35.1, 100 mg, 0.224 mmol) was dissolved in DMF (1.5 mL).4-Cyanopyridine-3-boronic acid pinacol ester (77 mg, 0.336 mmol), K₂CO₃(0.224 mL, 0.448 mmol) and Pd(PPh₃)₄ (12.95 mg, 0.011 mmol) were addedat RT. The vial was evacuated/purged with argon and sealed. The lightyellow solution was stirred at 130° C. for 4 h. The yellow reactionsolution was diluted with EtOAc (50 mL) and washed with water (3×30 mL).the combined extracts were dried over Na₂SO₄, filtered, the solvent wasevaporated off under reduced pressure to give a crude that was purifiedby flash chromatography (RediSep® Silica gel column, 24 g, DCM/MeOH95:5). The fractions containing product were evaporated to dryness underreduced pressure and the residue was dissolved in hot MeOH (2 mL). Theyellow solution was allowed to cool down to RT under stirring and theresulting suspension was stirred at RT for 1 h then filtered. The solidwas washed with MeOH (1 mL) and dried to afford the title product as awhite solid. HPLC (Condition 10) t_(R)=5.91 min, UPLC-MS (Condition 3)t_(R)=0.95 min, m/z=470 [M+H]⁺; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm1.65-1.97 (m, 2H) 2.84 (d, J=10.95 Hz, 1H) 3.07-3.18 (m, 1H) 3.19-3.30(m, 1H) 3.32-3.45 (m, 1H) 4.21 (br. s, 1H) 4.82-5.00 (m, 1H) 7.36 (d,J=8.99 Hz, 2H) 7.85 (d, J=8.99 Hz, 2H) 7.94-8.05 (m, 1H) 8.12 (d, J=6.26Hz, 1H) 8.80-8.90 (m, 2H) 9.03 (s, 1H) 10.21 (s, 1H).

Example 241(R)-6′-Amino-5′-fluoro-2-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 169 using(R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 35.1) and3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amineto afford a white amorphous powder. HPLC (Condition 4) t_(R)=4.37 min,UPLC-MS (Condition 3) t_(R)=0.91 min, m/z=478.1 [M+H]⁺; ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 1.66-1.89 (m, 2H) 2.94 (d, J=11.34 Hz, 1H) 3.18-3.28 (m,2H) 3.34-3.47 (m, 1H) 4.19 (br. s, 1H) 4.83 (d, J=3.13 Hz, 1H) 6.32 (s,2H) 7.32 (d, J=8.99 Hz, 2H) 7.40 (d, J=11.73 Hz, 1H) 7.77 (s, 1H) 7.83(d, J=8.99 Hz, 2H) 7.93 (m, J=2.30, 1.20 Hz, 1H) 8.64-8.72 (m, 1H) 10.11(s, 1H).

Example 242(R)-2′,6′-Difluoro-2-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-[3,4′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 169 using(R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 35.1) and 2,6-difluoropyridin-4-ylboronic acid to afford a whiteamorphous powder. HPLC (Condition 4) t_(R)=5.67 min, UPLC-MS (Condition3) t_(R)=1.10 min, m/z=481.1 [M+H]⁺; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm1.70-1.80 (m, 1H) 1.87 (m, J=9.00 Hz, 1H) 2.86 (d, J=11.34 Hz, 1H)3.18-3.29 (m, 2H) 3.47 (m, J=7.00 Hz, 1H) 4.22 (br. s, 1H) 4.87 (d,J=3.52 Hz, 1H) 7.23 (s, 2H) 7.34 (d, J=9.38 Hz, 2H) 7.78-7.89 (m, 2H)8.13 (d, J=2.35 Hz, 1H) 8.78 (d, J=2.35 Hz, 1H) 10.18 (s, 1H).

Example 243(R)—N-(4-(Chlorodifluoromethoxy)phenyl)-4-(3-hydroxypyrrolidin-1-yl)-3-(pyrimidin-5-yl)benzamide

(R)-3-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-(3-hydroxypyrrolidin-1-yl)benzamide(Stage 243.1, 80 mg, 0.173 mmol), pyrimidin-5-ylboronic acid (42.9 mg,0.347 mmol), Pd(PPh₃)₂Cl₂ (12.16 mg, 0.017 mmol) and Na₂CO₃ (73.5 mg,0.693 mmol) were added to a MW vial and treated with a mixture of DME(735 μL), water (210 μL) and EtOH (105 μL). The vial was sealed,evacuated/purged with argon and subjected to MW irradiation at 125° C.for 15 min, diluted with DCM (2 mL), treated with Si-Thiol (Silicycle,1.43 mmol/g, 72.2 mg, 0.104 mmol). The RM was centrifuged, thesupernatant was filtered and the solvent was evaporated off underreduced pressure to give a residue which was purified by flashchromatography (RediSep® Silica gel column, 12 g, DCM/MeOH+1% NH₄OH from1% to 10% MeOH+1% NH₄OH). Product was further purified by preparativeSFC (Column DEAP, isocratic 6% in 6 min) to yield the title product as awhite solid. UPLC-MS (Condition 3) t_(R)=1.01 min, m/z=461.1 [M+H]⁺,m/z=459.1 [M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.66-1.81 (m, 1H)1.82-1.94 (m, 1H) 2.68 (d, J=9.66 Hz, 1H) 2.98-3.10 (m, 2H) 3.18-3.27(m, 1H) 4.17-4.26 (m, 1H) 4.89 (d, J=3.55 Hz, 1H) 6.99 (d, J=8.80 Hz,1H) 7.33 (d, J=9.17 Hz, 2H) 7.82-7.90 (m, 3H) 7.95 (dd, J=8.80, 2.20 Hz,1H) 8.87 (s, 2H) 9.17 (s, 1H) 10.12 (s, 1H).

Stage 243.1(R)-3-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-(3-hydroxypyrrolidin-1-yl)benzamide

A mixture of3-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-fluorobenzamide (1 g, 2.53mmol), (R)-pyrrolidin-3-ol (0.331 g, 3.80 mmol) in TEA (0.706 mL, 5.07mmol) and DMSO (2.53 mL) was stirred at 90° C. for 20 h. The RM wastreated with 0.5 M HCl (50 mL) and extracted with EtOAc. The combinedextracts were washed with 0.5 M HCl, sat. aq. NaHCO₃ and brine, anddried over Na₂SO₄. The solvent was evaporated off under reduced pressureto give the crude product which was purified by flash chromatography(RediSep® Silica gel column, 40 g, cyclohexane/EtOAc, from 1% to 4.5%EtOAc). The residue was suspended in cyclohexane. The solid wasfiltered-off and dried to yield the title product as a white amorphoussolid. UPLC-MS (Condition 3) t_(R)=1.15 min, m/z=462.9 [M+H]⁺, m/z=460.9[M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.81-1.90 (m, 1H) 1.92-2.03 (m,1H) 3.27 (dd, J=10.39, 1.10 Hz, 1H) 3.36-3.44 (m, 1H) 3.62-3.71 (m, 1H)3.81 (dd, J=10.45, 4.71 Hz, 1H) 4.32-4.40 (m, 1H) 4.99 (d, J=3.42 Hz,1H) 6.93 (d, J=8.80 Hz, 1H) 7.33 (d, J=9.05 Hz, 2H) 7.82-7.91 (m, 3H)8.14 (d, J=2.20 Hz, 1H) 10.21 (s, 1H).

Stage 243.23-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-fluorobenzamide

The title compound was prepared in an analogous fashion to thatdescribed in Stage 1.2 using 3-bromo-4-fluorobenzoic acid and4-(chlorodifluoromethoxy)aniline to afford an off-white solid. UPLC-MS(Condition 3) t_(R)=1.25 min, m/z=394.0 [M+H]⁺, m/z=391.9 [M−H]⁻; ¹H-NMR(400 MHz, DMSO-d₆) δ ppm 7.37 (d, J=9.17 Hz, 2H) 7.57 (t, J=8.68 Hz, 1H)7.84-7.91 (m, 2H) 8.03 (ddd, J=8.62, 4.83, 2.32 Hz, 1H) 8.32 (dd,J=6.60, 2.20 Hz, 1H) 10.52 (s, 1H).

Example 244N-(4-(Chlorodifluoromethoxy)phenyl)-4-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)-3-(pyrimidin-5-yl)benzamide

3-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)benzamide(Stage 244.1, 80 mg, 0.167 mmol), pyrimidin-5-ylboronic acid (41.5 mg,0.335 mmol), Pd(PPh₃)₂Cl₂ (11.76 mg, 0.017 mmol) and Na₂CO₃ (71.0 mg,0.670 mmol) were added to a MW vial and treated with a mixture of DME(710 μL), water (203 μL) and EtOH (101 μL). The vial was sealed,evacuated/purged with argon and subjected to MW irradiation at 125° C.for 10 min, diluted with MeOH (1 mL) and DCM (2 mL), treated withSi-Thiol (Silicycle, 1.44 mmol/g, 69.8 mg, 0.1 mmol). The solvent wasevaporated off under reduced pressure to give a crude product that waspurified by flash chromatography (RediSep® Silica gel column, 12 g,DCM/(MeOH-1% NH₄OH), from 2% to 12% (MeOH-1% NH₄OH). Product was furtherpurified by preparative SFC (Column DEAP, from 25% to 30% in 10 min) toyield the title product as a white solid. UPLC-MS (Condition 3)t_(R)=0.90 min, m/z=476.9 [M+H]⁺, m/z=521.0 [M+formic acid−H]; ¹H-NMR(400 MHz, DMSO-d₆) δ ppm 2.75 (d, J=10.39 Hz, 2H) 3.27 (dd, J=10.33,3.61 Hz, 2H) 3.88 (br. s, 2H) 5.09 (d, J=3.18 Hz, 2H) 6.97 (d, J=8.93Hz, 1H) 7.33 (d, J=9.05 Hz, 2H) 7.82-7.90 (m, 3H) 7.94 (dd, J=8.80, 2.20Hz, 1H) 8.86 (s, 2H) 9.17 (s, 1H) 10.11 (s, 1H).

Stage 244.13-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)benzamide

The title compound was prepared in an analogous fashion to thatdescribed in Stage 243.1 (20 h at 90° C.+3 h at 105° C.) using3-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-fluorobenzamide and(3S,4S)-pyrrolidine-3,4-diol to afford a white amorphous solid. UPLC-MS(Condition 3) t_(R)=1.01 min, m/z=476.8 [M+H]⁺.

Example 2454-((3S,4S)-3-Amino-4-hydroxypyrrolidin-1-yl)-N-(4-(chlorodifluoromethoxy)phenyl)-3-(pyrimidin-5-yl)benzamide

4-((3S,4S)-3-amino-4-hydroxypyrrolidin-1-yl)-3-bromo-N-(4-(chlorodifluoromethoxy)phenyl)benzamide(Stage 245.1, 60 mg, 0.121 mmol), 5-pyrimidineboronic acid (22.46 mg,0.181 mmol) and Na₂CO₃ aq. (0.181 mL, 0.362 mmol) were added to a vialcontaining DME (1.5 mL) under argon atmosphere. PdCl₂(dppf)-(CH₂Cl₂)(5.92 mg, 7.25 μmol) was added. The RM was stirred at 80° C. for 2 h,then filtered through Hyflo® and the solvent was evaporated off underreduced pressure to give the crude product which was purified bypreparative HPLC (Condition 14). Fractions containing the product werecombined, treated with sat. aq. Na₂CO₃ and the MeCN was removed. The aq.residue was extracted with DCM and the combined extracts were dried overNa₂SO₄, filtered and the filtrate was evaporated off under reducedpressure to give a residue that was suspended in DCM/n-hexane. Theobtained solid was filtered off and washed with n-hexane then purifiedby SFC. The residue diluted with sat. aq. Na₂CO₃ (20 mL) and DCM (20mL). Aq. phase was extracted with DCM (2×10 mL) and with EtOAc (3×10mL). The combined extracts were dried over Na₂SO₄ and the solvent wasevaporated off under reduced pressure to afford the title product as abeige solid. HPLC (Condition 10) t_(R)=5.77 min, UPLC-MS (Condition 3)t_(R)=0.79 min, m/z=476.1/478.2 [M+H]⁺; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm2.65-2.73 (m, 2H) 3.09-3.15 (m, 1H) 3.21-3.30 (m, 2H) 3.71-3.79 (m, 1H)5.00 (d, J=3.50 Hz, 1H) 6.95 (d, J=8.99 Hz, 1H) 7.34 (d, J=8.20 Hz, 2H)7.83-7.90 (m, 3H) 7.94 (dd, J=8.60, 2.30 Hz, 1H) 8.86 (d, J=0.78 Hz, 2H)9.17 (d, J=1.17 Hz, 1H) 10.10 (s, 1H).

Stage 245.14-((3S,4S)-3-Amino-4-hydroxypyrrolidin-1-yl)-3-bromo-N-(4-(chlorodifluoromethoxy)phenyl)benzamide

3-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-fluorobenzamide (240 mg,0.596 mmol) and TEA (0.332 mL, 2.384 mmol) were added to a vialcontaining DMSO (0.5 mL). (3S,4S)-4-aminopyrrolidin-3-ol dihydrochloride(Stage 245.2, 128 mg, 0.715 mmol) was added. The RM was stirred at 100°C. for 40 h. The RM was treated with sat. aq. Na₂CO₃ (50 mL) and wasextracted with EtOAc. The combined extracts were washed with water (30mL) and brine (30 mL), dried over Na₂SO₄, filtered and the filtrate wasevaporated off under reduced pressure to give a crude product that waspurified by flash chromatography (from 100% EtOAc to EtOAc/EtOH/NH₃ aq.90:9:1) to afford the title product as a beige solid. HPLC (Condition10) t_(R)=6.08 min, UPLC-MS (Condition 3) t_(R)=0.82 min,m/z=476.1/478.1 [M+H]⁺.

Stage 245.2 (3S,4S)-4-Aminopyrrolidin-3-ol dihydrochloride

(3S,4S)-tert-Butyl 3-amino-4-hydroxypyrrolidine-1-carboxylate (0.3 g,1.439 mmol) in 1.25 M HCl 1.25 M in EtOH (11.51 mL, 14.39 mmol) wasstirred for 24 h at RT. The white suspension was evaporated to drynessunder reduced pressure and the residue was suspended in MeOH (10 mL) andevaporated again to afford the title compound.

Example 246N-(4-(Chlorodifluoromethoxy)phenyl)-4-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)-3-(2-methylpyrimidin-5-yl)benzamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 244 (only SFC purification) using3-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)benzamide(Stage 244.1) and 2-methylpyrimidin-5-ylboronic to afford a brown solid.UPLC-MS (Condition 3) t_(R)=0.91 min, m/z=491.1 [M+H]⁺, m/z=535.1[M+formic acid−H]; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 2.69 (s, 3H) 2.75 (d,J=10.39 Hz, 2H) 3.27 (dd, J=10.33, 3.73 Hz, 2H) 3.88 (br. s, 2H) 5.07(d, J=3.30 Hz, 2H) 6.94 (d, J=8.80 Hz, 1H) 7.33 (d, J=9.05 Hz, 2H) 7.82(d, J=2.32 Hz, 1H) 7.84-7.90 (m, 2H) 7.92 (dd, J=8.80, 2.32 Hz, 1H) 8.72(s, 2H) 10.09 (s, 1H).

Example 247N-(4-(Chlorodifluoromethoxy)phenyl)-6-(3,3-difluoropyrrolidin-1-yl)-5-(pyrimidin-5-yl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 224 using6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(pyrimidin-5-yl)nicotinamide(Stage 247.1) and 3,3-difluoropyrrolidine hydrochloride (no extractionwith citric acid). After purification by flash chromatography on Silicagel, the residue was suspended in iPr₂O (10 mL) and stirred for 30 min.Crystals were filtrated off, washed with iPr₂O (10 mL) and dried toafford the title product as a white solid. HPLC (Condition 10)t_(R)=7.198 min, UPLC-MS (Condition 3) t_(R)=1.12 min, m/z=482 [M+H]⁺;¹H-NMR (400 MHz, DMSO-d₆) δ ppm 2.39 (spt, J=7.14 Hz, 2H) 3.37 (t,J=7.23 Hz, 2H) 3.62 (t, J=12.90 Hz, 2H) 7.36 (d, J=8.21 Hz, 2H) 7.87 (d,J=8.99 Hz, 2H) 8.15 (s, 1H) 8.82 (s, 1H) 8.94 (s, 2H) 9.23 (s, 1H) 10.28(s, 1H).

Stage 247.16-Chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(pyrimidin-5-yl)nicotinamide

6-Chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-iodonicotinamide (Stage247.2, 8 g, 17.43 mmol), pyrimidine-5-boronic acid (4.55 g, 34.9 mmol),PdCl₂(dppf) (0.638 g, 0.871 mmol), Na₂CO₃ (26.1 mL of 2 M, 52.3 mmol),and DME (110 mL) were added to a vial, which was sealed,evacuated/purged with argon and the RM was stirred at 90° C. for 20 h.The RM was dissolved in EtOAc (200 mL), washed with water, dried overNa₂SO₄ and the solvent was evaporated off under reduced pressure. Theresidue was purified by flash chromatography (Silica gel column, 750 g,EtOAc/n-hexane 1:1) and recrystallized from EtOAc/iPr₂O to give thetitle product as a pink solid. HPLC (Condition 10) t_(R)=6.77 min,UPLC-MS (Condition 3) t_(R)=1.05 min, m/z=409.0/411.0 [M−H]⁻; ¹H-NMR(400 MHz, DMSO-d₆) δ ppm 6.59 (d, J=8.60 Hz, 2H) 7.07 (d, J=8.99 Hz, 2H)7.75 (d, J=1.95 Hz, 1H) 8.18-8.24 (m, 1H) 8.28 (s, 2H) 8.50 (s, 1H) 9.88(s, 1H).

Stage 247.26-Chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-iodonicotinamide

6-Chloro-5-iodo-3-pyridinecarboxylic acid (18 g, 62.2 mmol) wassuspended in toluene (125 mL). DMF (1.446 mL, 18.67 mmol) and SOCl₂(13.63 mL, 187 mmol) were added at RT. The RM was stirred at 80° C. for1 h, cooled to RT then the solvent was evaporated off under reducedpressure to give a residue that was dissolved in THF (125 mL) and cooledto −15° C. DIPEA (21.74 mL, 124 mmol) was added at −15° C., and the coldmixture was treated dropwise with a solution of4-(chlorodifluoromethoxy)aniline in THF (125 mL) over 12 min. Theresulting fine orange suspension was stirred for 1 h at RT. The solventwas evaporated off under reduced pressure and the residue was dissolvedin TBME (500 mL), and sequentially washed with 1N HCl (2×150 mL), sat.aq. NaHCO₃ solution (2×150 mL) and brine (2×150 mL). The aq. phases wereextracted with TBME (400 mL). Combined organic phases were dried overNa₂SO₄, filtered and concentrated under reduced pressure untilcrystallization began (around 100 mL). n-Heptane (800 mL) was then addedwith stirring and the light yellow suspension was stirred at RT for 30min. The crystalline product was filtrated, washed with n-heptane (200mL) and dried to afford the title product as a beige solid. LC-MS(Condition 3) t_(R) 1.25 min, 459.0/460.7/462.1 [M+H]⁺.

Example 248N-(4-(Chlorodifluoromethoxy)phenyl)-6-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)-5-(pyrimidin-5-yl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 244 using3-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)benzamide(Stage 244.1) and pyrimidin-5-ylboronic acid to afford an off-whitesolid. UPLC-MS (Condition 3) t_(R)=0.87 min, m/z=478.0 [M+H]⁺, m/z=476.0[M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 2.95 (d, J=11.49 Hz, 2H) 3.42(dd, J=11.43, 3.36 Hz, 2H) 3.88 (br. s, 2H) 5.09 (d, J=3.30 Hz, 2H) 7.35(d, J=9.05 Hz, 2H) 7.82-7.91 (m, 2H) 8.11 (d, J=2.32 Hz, 1H) 8.79 (d,J=2.32 Hz, 1H) 8.89 (s, 2H) 9.21 (s, 1H) 10.20 (s, 1H).

Stage 248.15-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)nicotinamide

A suspension of5-bromo-6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide (Stage169.2, 1 g, 2.427 mmol) and (3S,4S)-pyrrolidine-3,4-diol (0.3 g, 2.91mmol) in a mixture of DIPEA (1.272 mL, 7.28 mmol) and iPrOH (3.24 mL)was subjected to MW irradiation at 140° C. for 1 h. The RM was treatedwith 0.5 M HCl (40 mL) and extracted with EtOAc. The combined extractswere washed with water, sat. aq. NaHCO₃ and brine, dried over Na₂SO₄ andthe solvent was evaporated off under reduced pressure to give a residuethat was suspended in a mixture of cyclohexane EtOAc. The resultingsolid was filtered-off, washed with cyclohexane and dried to afford thetitle product as an off-white solid. UPLC-MS (Condition 3) t_(R)=0.98min, m/z=477.9 [M+H]⁺, m/z=475.8 [M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm3.55 (d, J=11.13 Hz, 2H) 3.91-4.09 (m, 4H) 5.18 (d, J=2.81 Hz, 2H) 7.34(d, J=9.05 Hz, 2H) 7.80-7.93 (m, 2H) 8.34 (d, J=1.96 Hz, 1H) 8.67 (d,J=1.96 Hz, 1H) 10.24 (s, 1H).

Example 249N-(4-(Chlorodifluoromethoxy)phenyl)-6-(cis-3,4-dihydroxypyrrolidin-1-yl)-5-(pyrimidin-5-yl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 244 using5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(cis-3,4-dihydroxypyrrolidin-1-yl)nicotinamide(Stage 249.1) and pyrimidin-5-ylboronic acid to afford a white solid.UPLC-MS (Condition 3) t_(R)=0.87 min, m/z=478.1 [M+H]⁺, m/z=476.1[M−H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 3.05 (dd, J=11.00, 4.40 Hz, 2H)3.26 (dd, J=10.64, 5.26 Hz, 2H) 3.94-4.02 (m, 2H) 4.88 (d, J=4.65 Hz,2H) 7.34 (d, J=9.05 Hz, 2H) 7.81-7.90 (m, 2H) 8.10 (d, J=2.20 Hz, 1H)8.79 (d, J=2.20 Hz, 1H) 8.88 (s, 2H) 9.20 (s, 1H) 10.18 (s, 1H).

Stage 249.15-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(cis-3,4-dihydroxypyrrolidin-1-yl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Stage 71.1 using5-bromo-6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide (Stage169.2) and cis-pyrrolidine-3,4-diol (Stage 249.2). After purification byflash chromatography on Silica gel, the oily residue was taken-up in atoluene/MeOH mixture then evaporated to dryness under reduced pressureand dried to yield the title product as a white amorphous solid. UPLC-MS(Condition 3) t_(R)=1.0 min, m/z=477.8-479.9 [M+H], m/z=475.8-477.9[M−H].

Stage 249.2 cis-Pyrrolidine-3,4-diol

To a solution of benzyl 2,5-dihydro-1H-pyrrole-1-carboxylate (5 g, 22.14mmol) in THF (33 mL) and water (8.3 mL) were addedN-methylmorpholine-N-oxide (2.85 g, 24.36 mmol) and osmium tetroxide,2.5% wt solution in 2-methyl-2-propanol (3.34 mL, 0.266 mmol). The RMwas stirred at RT for 16 h. The solvent was evaporated off under reducedpressure and the residue was treated with EtOAc (100 mL), was washedwith aq. Na₂SO₃ (1 g in 30 mL water), aq. NaHCO₃, and brine. Thecombined aq. phases were back-extracted with EtOAc (30 mL) and thecombined organic phases were dried over Na₂SO₄ and evaporated to drynessunder reduced pressure to give the crude product which was purified byflash chromatography (Biotage SNAP Silica gel column, 100 g, DCM/MeOH,from 2% to 7% MeOH). To a solution of part of previous product (2.373 g,10 mmol) in MeOH (50 mL) was added NP Pd(0)EnCat™ 30, 0.4 mmol Pd/g (1.5g, 0.6 mmol). The vial was evacuated/purged with argon and the mixturewas stirred at RT for 16 h under a hydrogen atmosphere. The catalyst wasfiltered off and the solvent was evaporated off under reduced pressureto afford the title product as a dark red oil, which was used in thenext step without further purification. ESI+/−(120-1200): m/z=104.1[M+H]⁺.

Example 250N-(4-(Chlorodifluoromethoxy)phenyl)-6-(trans-3-hydroxy-4-(hydroxymethyl)pyrrolidin-1-yl)-5-(pyrimidin-5-yl)nicotinamide

A suspension of6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(pyrimidin-5-yl)nicotinamide(Stage 247.1, 80 mg, 0.195 mmol), trans-4-(hydroxymethyl)pyrrolidin-3-ol(+/−), hydrochloride (80 mg, 0.521 mmol) in a mixture of DIPEA (136 μL,0.778 mmol) and iPrOH (389 μL) was subjected to MW irradiation at 140°C. for 1.5 h. The RM was treated with water (10 mL) and extracted withEtOAc. The combined extracts were washed with sat. NaHCO₃ and brine,dried over Na₂SO₄ and the solvent was evaporated off under reducedpressure to give a crude product that was purified by preparative SFC(Column DEAP, from 22% to 27% in 10 min) to yield the title product as awhite solid. UPLC-MS (Condition 3) t_(R)=0.86 min, m/z=492.1 [M+H]⁺,m/z=536.2 [M+formic acid−H]; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 2.04-2.14(m, 1H) 2.89 (dd, J=11.13, 3.91 Hz, 1H) 3.10 (dd, J=11.13, 5.26 Hz, 1H)3.20-3.29 (m, 2H) 3.34-3.48 (m, 2H) 3.92-4.01 (m, 1H) 4.63 (t, J=5.26Hz, 1H) 4.98 (d, J=4.40 Hz, 1H) 7.35 (d, J=9.05 Hz, 2H) 7.81-7.90 (m,2H) 8.10 (d, J=2.45 Hz, 1H) 8.80 (d, J=2.32 Hz, 1H) 8.90 (s, 2H) 9.20(s, 1H) 10.19 (s, 1H).

Example 251-265

The following examples were prepared in an analogous fashion to thatdescribed in the Example using the Stage as indicated.

Example/Stage and starting material Ex. Structure/Name Analytics 251

225/247.1 and (3S,4S)-4- (dimethylamino)pyrrolidin-3-ol HPLC (Condition10) t_(R) = 5.75 min, UPLC-MS (Condition 3) t_(R) = 0.77 min, m/z =505.1/507.0 [M + H]⁺; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 2.16 (br. s, 6 H)2.50 (d, J = 0.78 Hz, 1 H) 2.86 (dd, J = 10.75, 5.28 Hz, 1 H) 3.15-3.31(m, 2 H) 3.38- 3.56 (m, 1 H) 4.10 (br. s, 1 H) 7.35 (d, J = 8.99 Hz, 2H) 7.86 (d, J = 9.38 Hz, 2 H) 8.08-8.17 (m, 1 H) 8.80 (d, J = 2.35 Hz, 1H) 8.90 (s, 2 H) 9.21 (s, 1 H) 10.20 (s, 1 H). 252

226/247.1 and tert-butyl 3- azabicyclo[3.1.0]hexan-1-ylcarbamate HPLC(Condition 4) t_(R) = 4.34 min, UPLC-MS (Condition 3) t_(R) = 0.78 min,m/z = 473.1 [M + H]⁺; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 0.31 (t, J = 4.50Hz, 1 H) 0.77 (dd, J = 8.21, 4.69 Hz, 1 H) 1.27-1.40 (m, 1 H) 3.10 (d, J= 10.17 Hz, 1 H) 3.32-3.51 (m, 5 H) 7.32 (d, J = 8.99 Hz, 2 H) 7.83 (d,J = 9.38 Hz, 2 H) 8.05 (d, J = 2.35 Hz, 1 H) 8.75 (d, J = 2.35 Hz, 1 H)8.89 (d, J = 0.78 Hz, 2 H) 9.20 (s, 1 H) 10.18 (s, 1 H). 253

226/247.1 and tcrt-butyl (1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-ylcarbamate HPLC (Condition 4) t_(R) = 4.45min, UPLC-MS (Condition 3) t_(R) = 0.77 min, m/z = 473 [M + H]⁺; ¹H-NMR(400 MHz, DMSO-d₆) δ ppm 1.40 (br. s, 2 H) 1.84 (s, 2 H) 3.16-3.25 (m, 2H) 3.28- 3.40 (m, 3 H) 7.32 (d, J = 8.60 Hz, 2 H) 7.77-7.86 (m, 2 H)8.02 (d, J = 2.35 Hz, 1 H) 8.75 (d, J=2.35 Hz, 1 H) 8.86 (s, 2 H) 9.19(s, 1 H) 10.17 (s, 1 H). 254

225/247.1 and 1,4,5,6-tetrahydropyrrolo[3,4- c]pyrazole HPLC (Condition10) t_(R) = 6.10 min, UPLC-MS (Condition 3) t_(R) = 0.96 min, m/z = 484[M + H]⁺; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 4.30 (s, 2H) 4.33 (s, 2H) 7.33(d, J = 8.60 Hz, 2 H) 7.48 (s, 1 H) 7.85 (d, J = 8.60 Hz, 2 H) 8.07 (d,J = 2.35 Hz, 1 H) 8.86 (d, J = 2.35 Hz, 1 H) 8.97 (s, 2 H) 9.24 (s, 1 H)10.22 (s, 1 H) 12.65 (br. s, 1 H). 255

226/247.1 and R-3-(Boc-amino)piperidine HPLC (Condition 10) t_(R) = 5.86min, UPLC-MS (Condition 3) t_(R) = 0.79 min, m/z = 475.1/477.1 [M + H]⁺;¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.03-1.16 (m, 1 H) 1.27-1.48 (m, 2 H)1.49- 1.59 (m, 1 H) 1.74-1.85 (m, 1 H) 2.40-2.51 (m, 2 H) 2.54-2.64 (m,1 H) 2.64-2.74 (m, 1 H) 3.39-3.57 (m, 2 H) 7.36 (d, J = 8.60 Hz, 2 H)7.86 (d, J = 9.38 Hz, 2 H) 8.18 (d, J = 2.35 Hz, 1 H) 8.80 (d, J = 2.35Hz, 1 H) 9.07 (s, 2 H) 9.20 (s, 1 H) 10.31 (s. 1 H). 256

226/247.1 and tert-butyl 4,7- diazaspiro[2.5]octane-4-carboxylate HPLC(Condition 4) t_(R) = 4.37 min, UPLC-MS (Condition 3) t_(R) = 0.80 min,m/z = 487.1 [M + H]⁺; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 0.20- 0.28 (m, 2H) 0.32-0.41 (m, 2 H) 2.25-2.42 (m, 1 H) 2.60-2.69 (m, 2 H) 2.99 (s, 2H) 3.04-3.09 (m, 2 H) 7.34 (d, J = 8.21 Hz, 2 H) 7.79-7.89 (m, 2 H) 8.17(d, J = 2.35 Hz, 1 H) 8.74-8.82 (m, 1 H) 9.01-9.09 (m, 2 H) 9.19 (d, J =0.78 Hz, 1 H) 10.31 (s, 1 H). 257

250/247.1 and trans-4- (hydroxymethyl)piperidin-3-ol UPLC-MS (Condition3) t_(R) = 0.90 min, m/z = 505.9 [M + H]⁺, m/z = 503.9 [M − H]⁻; ¹H-NMR(400 MHz, DMSO-d₆) δ ppm 1.14-1.27 (m, 1 H) 1.41-1.52 (m, 1 H) 1.52-1.61(m, 1 H) 2.71- 2.80 (m, 1 H) 2.91 (d, J = 11.86 Hz, 1 H) 3.21- 3.29 (m,1 H) 3.42 (m, J = 5.56, 3.85 Hz, 1 H) 3.54- 3.69 (m, 2 H) 3.78 (br. s, 1H) 4.35 (t, J = 5.26 Hz, 1 H) 4.45 (d, J = 3.91 Hz, 1 H) 7.36 (d, J =9.05 Hz, 2 H) 7.82-7.90 (m, 2 H) 8.17 (d, J = 2.45 Hz, 1 H) 8.77 (d, J =2.45 Hz, 1 H) 9.10 (s, 2 H) 9.19 (s, 1 H) 10.30 (s, 1 H) 258

224/247.1 and 3-hydroxyazetidine hydrochloride HPLC (Condition 10) t_(R)= 5.61 min, UPLC-MS (Condition 3) t_(R) = 0.90, m/z = 448 [M + H]⁺; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 3.50 (dd, J = 9.38, 4.30 Hz, 2 H) 3.85-3.97(m, 2 H) 4.35- 4.44 (m, 1 H) 5.59 (d, J = 6.26 Hz, 1 H) 7.35 (d, J =8.99 Hz, 2 H) 7.84 (d, J = 8.99 Hz, 2 H) 8.10 (dd, J = 2.35, 0.78 Hz, 1H) 8.80 (dd, J = 2.15, 0.98 Hz, 1 H) 8.92 (d, J = 0.78 Hz, 2 H) 9.23 (d,J = 0.78 Hz, 1 H) 10.23 (s, 1 H). 259

226/247.1 and tert-butyl azetidin-3-ylcarbamate HPLC (Condition 10)t_(R) = 5.64 min, UPLC-MS (Condition 3) t_(R) = 0.76 min, m/z =447.0/449.0 [M + H]⁺; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 3.37 (dd, J =8.99, 5.47 Hz, 2 H) 3.57-3.67 (m, 1 H) 3.85 (t, J = 8.02 Hz, 2 H) 7.35(d, J = 8.60 Hz, 2 H) 7.86 (m, J = 9.00 Hz, 2 H) 8.08 (d, J = 2.35 Hz, 1H) 8.79 (d, J = 2.35 Hz, 1 H) 8.91 (s, 2 H) 9.22 (s, 1 H) 10.20 (s, 1H). 260

224/247.1 and 3-azetidinemethanol hydrochloride HPLC (Condition 10)t_(R) = 5.54 min, UPLC-MS (Condition 3) t_(R) = 0.91 min, m/z = 462.1[M + H]⁺; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 2.56- 2.70 (m, 1 H) 3.40-3.55(m, 4 H) 3.74 (t, J = 8.41 Hz, 2 H) 4.71 (t, J = 5.28 Hz, 1 H) 7.35 (d,J = 8.99 Hz, 2 H) 7.81-7.90 (m, 2 H) 8.08 (d, J = 2.35 Hz, 1 H) 8.79 (d,J = 2.35 Hz, 1 H) 8.92 (s, 2 H) 9.22 (s, 1 H) 10.21 (s, 1 H). 261

224/247.1 and diethanolamine HPLC (Condition 10) t_(R) = 5.52 min,UPLC-MS (Condition 3) t_(R) = 0.76 min, m/z = 480 [M + H]⁺; ¹H-NMR (400MHz, DMSO-d₆) δ ppm 2.64 (t, J = 5.67 Hz, 2 H) 2.96 (t, J = 5.67 Hz, 2H) 3.44 (q, J = 5.47 Hz, 2 H) 4.51 (t, J = 5.47 Hz, 2 H) 7.39 (d, J =8.60 Hz, 2 H) 7.85-7.93 (d, J = 8.60 Hz, 2 H) 7.87 8.50 (d, J = 2.35 Hz,1 H) 8.84 (d, J = 2.35 Hz, 1 H) 9.18 (s, 2 H) 9.22 (s, 1 H) 10.47 (s, 1H). 262

244/248.1 and 2-methylpyrimidin-5-ylboronic acid UPLC-MS (Condition 3)t_(R) = 0.87 min, m/z = 492.1 [M + H]⁺, m/z = 536.1 [M + formic acid −H]⁻; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 2.69 (s, 3 H) 2.96 (d, J = 11.49Hz, 2 H) 3.42 (dd, J = 11.49, 3.42 Hz, 2 H) 3.88 (br. s, 2 H) 5.08 (d, J= 3.18 Hz, 2 H) 7.35 (d, J = 9.05 Hz, 2 H) 7.82-7.90 (m, 2 H) 8.06 (d, J= 2.32 Hz, 1 H) 8.75 (s, 2 H) 8.77 (d, J = 2.32 Hz, 1 H) 10.18 (s, 1 H).263

282/171.1 and 297.1 UPLC-MS (Condition 3), t_(R) = 0.94 min, m/z =476.1/478.1 [M + H]⁺; ¹H-NMR (600 MHz, DMSO-d₆) δ ppm 1.66-1.92 (m, 2 H)2.18-2.38 (m, 3 H) 2.75-3.35 (m, 4 H) 4.13-4.24 (m, 1 H) 4.83-4.96 (m, 1H) 7.34 (d, J = 8.47 Hz, 2 H) 7.85 (d, J = 8.85 Hz, 2 H) 7.97-8.04 (m, 1H) 8.64- 8.85 (m, 2 H) 9.08 (s, 1 H) 10.11-10.20 (m, 1 H). 264

244/249.1 and 5-fluoropyridin-3-ylboronic acid (purification bypreparative SFC) UPLC-MS (Condition 3) t_(R) = 0.96 min, m/z = 495.1[M + H]⁺, m/z = 539.1 [M+ formic acid − H]; ¹H-NMR (400 MHz, DMSO-d₆) δppm 3.05 (dd, J = 10.88, 4.28 Hz, 2 H) 3.25 (dd, J = 10.76, 5.38 Hz, 2H) 3.97 (br. s, 2 H) 4.87 (s, 2 H) 7.34 (d, J = 9.29 Hz, 2 H) 7.79-7.84(m, 1 H) 7.84-7.89 (m, 2 H) 8.08 (d, J = 2.20 Hz, 1 H) 8.50 (t, 1 H)8.61 (d, J = 2.69 Hz, 1 H) 8.78 (d, J = 2.20 Hz, 1 H) 10.18 (s, 1 H).265

244/248.1 and 5-fluoropyridin-3-ylboronic acid UPLC-MS (Condition 3)t_(R) = 0.96 min, m/z = 495.0 [M + H]⁺, m/z = 492.9 [M − H]⁻; ¹H-NMR(400 MHz, DMSO-d₆) δ ppm 2.95 (d, J = 11.62 Hz, 2 H) 3.42 (dd, J =11.43, 3.24 Hz, 2 H) 3.87 (br. s, 2 H) 5.08 (d, J = 2.45 Hz, 2 H) 7.34(d, J = 9.05 Hz, 2 H) 7.79-7.92 (m, 3 H) 8.09 (d, J = 2.32 Hz, 1 H) 8.50(s, 1 H) 8.61 (d, J = 2.69 Hz, 1 H) 8.78 (d, J = 2.32 Hz, 1 H) 10.19 (s,1 H).

Example 2662-((3S,4S)-3-Amino-4-hydroxypyrrolidin-1-yl)-N-(4-(chlorodifluoromethoxy)phenyl)-5′-fluoro-[3,3′-bipyridine]-5-carboxamide

2-Chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5′-fluoro-[3,3′-bipyridine]-5-carboxamide(Stage 266.1, 70 mg, 0.160 mmol) and DIPEA (0.196 mL, 1.121 mmol) wereadded to a vial containing iPrOH (2 mL). (3S,4S)-4-Aminopyrrolidin-3-ol(30 mg, 0.168 mmol) was added. The mixture was stirred at 80° C. for 44h. The RM was treated with sat. aq. Na₂CO₃ (20 mL) and extracted withEtOAc. The combined extracts were washed with brine (10 mL), dried overNa₂SO₄, filtered and evaporated to dryness under reduced to give thecrude product which was purified by flash chromatography (Silica gelcolumn, 4 g, DCM/MeOH, from 95:5 to 8:2) to afford the title product asa beige solid. HPLC (Condition 10) t_(R)=5.83 min, UPLC-MS (Condition 3)t_(R)=0.81 min, m/z=494.2/496.2 [M+H]⁺; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm2.91 (dd, J=11.53, 2.93 Hz, 1H) 3.22-3.28 (m, 1H) 3.36-3.46 (m, 2H)3.59-3.66 (m, 1H) 4.02-4.08 (m, 1H) 5.48 (d, J=3.91 Hz, 1H) 7.35 (d,J=8.60 Hz, 2H) 7.87 (m, J=9.00 Hz, 3H) 8.13 (d, J=2.35 Hz, 1H) 8.55 (s,1H) 8.64 (d, J=2.74 Hz, 1H) 8.79-8.83 (m, 1H) 10.22 (s, 1H).

Stage 266.12-Chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5′-fluoro-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Stage 247.1 using6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-iodonicotinamide (Stage247.2) and 3-Fluoropyridine-5-boronic acid pinacolester (80° C. insteadof 90° C.) to afford a white solid. UPLC-MS (Condition 3) t_(R)=1.17min, m/z=428.0/429.9 [M+H]⁺.

Example 2672-(3-(Aminomethyl)-4-hydroxypyrrolidin-1-yl)-N-(4-(chlorodifluoromethoxy)phenyl)-5′-fluoro-[3,3′-bipyridine]-5-carboxamide

2-Chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5′-fluoro-[3,3′-bipyridine]-5-carboxamide(Stage 266.1, 80 mg, 0.183 mmol) and DIPEA (0.224 mL, 1.282 mmol) wereadded to a vial containing iPrOH (2 mL) and4-(aminomethyl)pyrrolidin-3-ol dihydrochloride (Stage 267.1, 37.1 mg,0.192 mmol) was added under an argon atmosphere. The RM was stirred at80° C. for 3 days. The RM was treated with sat. aq. Na₂CO₃ (20 mL) andextracted with EtOAc. The combined extracts were washed with brine (10mL), dried over Na₂SO₄, filtered and evaporated to dryness under reducedpressure to give the crude product was purified by preparative HPLC(Condition 14). Fractions containing product were treated with sat. aq.Na₂CO₃ and the MeCN was evaporated off under reduced pressure. Theresulting aq. residue was extracted with EtOAc and the combined extractswere dried over Na₂SO₄, filtered and evaporated. The residue wassuspended in DCM/Et₂O/n-hexane. The obtained solid was filtered off,washed with Et₂O, n-hexane and dried to afford the title product as awhite solid. HPLC (Condition 10) t_(R)=5.74 min, UPLC-MS (Condition 3)t_(R)=0.83 min, m/z=508 [M+H]⁺; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm2.41-3.33 (m, 7H) 3.92-4.21 (m, 1H) 7.34 (d, J=8.99 Hz, 2H) 7.85 (d,J=9.38 Hz, 3H) 8.03-8.11 (m, 1H) 8.47-8.54 (m, 1H) 8.59 (m, J=2.70 Hz,1H) 8.77 (m, J=2.30 Hz, 1H) 10.19 (s, 1H).

Stage 267.1 4-(Aminomethyl)pyrrolidin-3-ol dihydrochloride

A mixture of 1-N-Boc-cis-(3-(aminomethyl)-4-hydroxy)pyrrolidine (0.3 g,1.359 mmol) and HCl in EtOH (10.87 mL, 13.59 mmol) were stirred at RTfor 24 h. the solvent was evaporated off under reduced pressure and theresidue was suspended in n-hexane, filtered, washed with n-hexane anddried to afford the crude title product as a grey solid.

Example 268-277

Example/Stage and starting material Ex. Structure/Name Analytics 268

244/249.1 and 3-cyanopyridine-5-boronic acid UPLC-MS (Condition 3) t_(R)= 0.95 min, m/z = 502.1 [M + H]⁺, m/z = 546.1 [M + formic acid − H];¹H-NMR (400 MHz, DMSO-d₆) δ ppm 3.03 (dd, J = 10.88, 4.16 Hz, 2 H)3.19-3.28 (m, 2 H) 3.91- 4.02 (m, 2 H) 4.90 (d, J = 4.89 Hz, 2 H) 7.35(d, J = 9.17 Hz, 2 H) 7.82-7.92 (m, 2 H) 8.10 (d, J = 2.32 Hz, 1 H) 8.39(t, J = 2.08 Hz, 1 H) 8.79 (d, J = 2.32 Hz, 1 H) 8.89 (d, J = 2.20 Hz, 1H) 9.04 (d, J = 1.96 Hz, 1 H) 10.19 (s, 1 H). 269

244/248.1 and 3-cyanopyridine-5-boronic acid pinacol ester to afford anoff-white solid. UPLC- MS (Condition 3) t_(R) = 0.93 min, m/z = 502.1[M + H]⁺, m/z = 546.1[M + formic acid − H]; ¹H- NMR (400 MHz, DMSO-d₆) δppm 2.93 (d, J = 11.37 Hz, 2 H) 3.41 (dd, J = 11.49, 3.18 Hz, 2 H)3.84-3.91 (m, 2 H) 5.08 (d, J = 3.30 Hz, 2 H) 7.35 (d, J = 9.17 Hz, 2 H)7.82-7.90 (m, 2 H) 8.10 (d, J = 2.45 Hz, 1 H) 8.42 (s, 1 H) 8.79 (d, J =2.32 Hz, 1 H) 8.89 (d, J = 1.83 Hz, 1 H) 9.04 (d, J = 1.96 Hz, 1 H)10.19 (s, 1 H). 270

169/171.1 and2-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine HPLC (Condition 4) t_(R) = 4.29 min,UPLC-MS (Condition 3) t_(R) = 0.91 min, m/z = 475 [M + H]⁺; ¹H-NMR (400MHz, DMSO-d₆) δ ppm 1.60- 1.90 (m, 2 H) 2.13-2.35 (m, 3 H) 2.93 (d, J =11.34 Hz, 1 H) 3.02-3.22 (m, 3 H) 4.17 (br. s, 1 H) 4.76-4.91 (m, 1 H)7.24-7.37 (m, 3 H) 7.59-7.80 (m, 1 H) 7.81-7.87 (m, 2 H) 7.91 (d, J =1.96 Hz, 1 H) 8.47 (d, J = 4.69 Hz, 1 H) 8.76 (dd, J = 2.35, 0.78 Hz, 1H) 10.07-10.14 (m, 1 H). 271

169/171.1 and 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine to afford a white amorphouspowder. HPLC (Condition 4) t_(R) = 4.57 min, UPLC-MS (Condition 3) t_(R)= 0.95 min, m/z = 494 [M + H]⁺; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm1.64-1.89 (m, 2 H) 2.94 (d, J = 11.34 Hz, 1 H) 3.19-3.54 (m, 4 H) 4.19(br. s, 1 H) 6.36 (br. s, 2 H) 7.31 (d, J = 8.99 Hz, 2 H) 7.41 (dd, J =11.93, 1.76 Hz, 1 H) 7.77 (s, 1 H) 7.80-7.89 (m, 2 H) 7.94 (d, J = 2.35Hz, 1 H) 8.68 (d, J = 2.35 Hz, 1 H) 10.12 (s, 1 H). 272

169/171.1 and 2,5-difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) HPLC (Condition 4) t_(R) = 5.9 min,UPLC-MS (Condition 3) t_(R) = 1.08 min, m/z = 497.2 [M + H]⁺; ¹H-NMR(400 MHz, DMSO-d₆) δ ppm 1.67- 1.91 (m, 2 H) 2.88-2.99 (m, 1 H) 3.23(br. s, 2 H) 3.35-3.48 (m, 1 H) 4.15-4.26 (m, 1 H) 4.81- 4.92 (m, 1 H)7.31 (d, J = 1.00 Hz, 2 H) 7.39-7.55 (m, 1 H) 7.84 (d, J = 8.99 Hz, 2 H)8.09 (d, J = 1.96 Hz, 1 H) 8.33 (s, 1 H) 8.73-8.84 (m, 1 H) 10.18 (s, 1H). 273

169/171.1 and 2,6-difluoropyridin-4-ylboronic acid HPLC (Condition 4)t_(R) = 5.83 min, UPLC-MS (Condition 3) t_(R) = 1.13 min, m/z = 497.1[M + H]⁺; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.71- 1.81 (m, 1 H) 1.87 (m, J= 8.60, 4.30 Hz, 1 H) 2.86 (d, J = 11.34 Hz, 1 H) 3.21-3.29 (m, 2 H)3.47 (m, J = 7.40 Hz, 1 H) 4.22 (br. s, 1 H) 4.87 (d, J = 2.74 Hz, 1 H)7.24 (s, 2 H) 7.33 (d, J = 8.60 Hz, 2 H) 7.79-7.90 (m, 2 H) 8.13 (d, J =2.35 Hz, 1 H) 8.78 (d, J = 2.35 Hz, 1 H) 10.18 (s, 1 H). 274

240/171.1 and 4-cyanopyridine-3-boronic acid pinacol ester. HPLC(Condition 10) t_(R) = 6.06 min, UPLC-MS (Condition 3) t_(R) = 0.99 min,m/z = 486 [M + H]⁺; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.65- 1.98 (m, 2 H)2.85 (d, J = 10.95 Hz, 1 H) 3.08- 3.19 (m, 1 H) 3.19-3.45 (m, 2 H)4.14-4.26 (m, 1 H) 4.82-4.98 (m, 1 H) 7.35 (d, J = 8.60 Hz, 2 H) 7.86(d, J = 8.99 Hz, 2 H) 7.94-8.05 (m, 1 H) 8.12 (d, J = 7.04 Hz, 1 H)8.79-9.08 (m, 3 H) 10.22 (s, 1 H). 275

245/215.1 and 3-fluoropyridine-5-boronic acid pinacol ester HPLC(Condition 10) t_(R) = 5.83 min, UPLC-MS (Condition 3) t_(R) = 0.94 min,m/z = 459.1 [M + H]⁺; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.69- 1.79 (m, 1H) 1.80-1.88 (m, 1 H) 1.88-1.99 (m, 3 H) 2.87 (d, J = 11.34 Hz, 1 H)3.17-3.28 (m, 2 H) 3.35-3.45 (m, 1 H) 4.21 (br. s, 1 H) 4.86 (dd, J =3.52, 1.17 Hz, 1 H) 7.17 (d, J = 8.60 Hz, 2 H) 7.75 (d, J = 8.99 Hz, 2H) 7.80-7.86 (m, 1 H) 8.07 (dd, J = 2.35, 1.17 Hz, 1 H) 8.50-8.53 (m, 1H) 8.58-8.61 (m, 1 H) 8.77 (dd, J = 2.35, 1.17 Hz, 1 H) 10.07 (s, 1 H).276

245/215.1 and 3-cyanopyridine-5-boronic acid pinacol ester HPLC(Condition 10) t_(R) = 5.85 min, UPLC-MS (Condition 3) t_(R) = 0.94 min,m/z = 466.3 [M + H]⁺; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.70 - 1.79 (m, 1H) 1.81 - 1.90 (m, 1 H) 1.93 (t, J=13.88 Hz, 3 H) 2.87 (d, J = 11.34 Hz,1 H) 3.17- 3.26 (m, 2 H) 3.34-3.43 (m, 1 H) 4.21 (br. s, 1 H) 4.88 (d, J= 3.52 Hz, 1 H) 7.18 (d, J = 8.99 Hz, 2 H) 7.76 (m, J = 9.00 Hz, 2 H)8.09 (d, J = 2.35 Hz, 1 H) 8.37-8.43 (m, 1 H) 8.79 (d, J = 2.35 Hz, 1 H)8.90 (d, J = 2.35 Hz, 1 H) 9.02 (d, J = 1.96 Hz, 1 H) 10.08 (s, 1 H).277

169/216.1 and 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine HPLC (Condition 4) t_(R) = 5.42 min,UPLC-MS (Condition 3) t_(R) = 1.05 min, m/z = 505.1 [M + H]⁺; ¹H-NMR(400 MHz, DMSO-d₆) δ ppm 1.69- 1.78 (m, 1 H) 1.80-1.91 (m, 1 H)2.81-2.91 (m, 1 H) 3.16-3.27 (m, 2 H) 3.34-3.45 (m, 1 H) 4.15-4.24 (m, 1H) 4.86 (d, J = 3.13 Hz, 1 H) 7.77- 7.91 (m, 3 H) 7.92-8.00 (m, 2 H)8.05-8.11 (m, 1 H) 8.50 (d, J = 1.17 Hz, 1 H) 8.56-8.61 (m, 1 H)8.74-8.82 (m, 1 H) 10.36 (s, 1 H).

Example 278(R)—N-(4-(2-Chloro-1,1,2,2-tetrafluoroethyl)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5-(pyrimidin-5-yl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 169 using(R)-5-bromo-N-(4-(2-chloro-1,1,2,2-tetrafluoroethyl)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide(Stage 278.1) and pyrimidin-5-ylboronic acid to afford an amorphouswhite powder. HPLC (Condition 4) t_(R)=5.21 min, UPLC-MS (Condition 3)t_(R)=0.99 min, m/z=496.1 [M+H]⁺; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm1.66-1.77 (m, 1H) 1.78-1.89 (m, 1H) 2.82-2.92 (m, 1H) 3.14-3.26 (m, 2H)3.32-3.42 (m, 1H) 4.15-4.26 (m, 1H) 4.87 (d, J=3.13 Hz, 1H) 7.63 (d,J=8.99 Hz, 2H) 7.97 (d, J=8.60 Hz, 2H) 8.10 (dd, J=2.35, 0.78 Hz, 1H)8.79 (dd, J=2.35, 0.78 Hz, 1H) 8.88 (d, J=0.78 Hz, 2H) 9.18 (d, J=0.78Hz, 1H) 10.31 (s, 1H).

Stage 278.1(R)-5-Bromo-N-(4-(2-chloro-1,1,2,2-tetrafluoroethyl)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Stage 171.1 using5-bromo-6-chloro-N-(4-(2-chloro-1,1,2,2-tetrafluoroethyl)phenyl)nicotinamide(Stage 278.2) and (R)-pyrrolidin-3-ol to afford a white powder. HPLC(Condition 4) t_(R)=6.05 min, UPLC-MS (Condition 3) t_(R)=1.18 min,m/z=498 [M+H]⁺.

Stage 278.25-Bromo-6-chloro-N-(4-(2-chloro-1,1,2,2-tetrafluoroethyl)phenyl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Stage 169.2 using4-(2-chloro-1,1,2,2-tetrafluoroethyl)aniline (Stage 278.3) and5-bromo-6-chloronicotinic acid to afford a beige crystalline powder.HPLC (Condition 4) t_(R)=6.77 min, UPLC-MS (Condition 3) t_(R)=1.31 min,m/z=444.8 [M−H]⁻.

Stage 278.3 4-(2-Chloro-1,1,2,2-tetrafluoroethyl)aniline

Ni(PPh3)₄ (222 mg, 0.2 mmol) was added to a mixture of aniline (745 mg,8 mmol) and 1-chloro-1,1,2,2-tetrafluoro-2-iodoethane (1049 mg, 4 mmol)in DMF (10 mL) in a MW vial under an argon atmosphere. The vial wassealed and the RM was stirred for two days at 80° C. After cooling atRT, the RM was dissolved in Et₂O, washed with NaHCO₃ 10% and brine,dried over MgSO₄ and the solvent was evaporated off under reducepressure to give a residue which was purified by flash chromatography(RediSep® Silica gel column, n-heptane/EtOAc, from 0 to 25% EtOAc) andfurther by reverse phase chromatography (MPLC, Lichroprep® 15-25 μmcolumn, eluents: water+0.1% formic/MeCN+0.1% formic acid, gradient 10 to50% MeCN+0.1% formic acid). The fractions containing pure product werecombined and the MeCN was evaporated off under reduced pressure to givean aq. phase which was neutralized with NaHCO₃ and extracted with Et₂O.The combined extracts were dried over MgSO₄ and the solvent wasevaporated off under reduced pressure to afford the title compound as ared oil. HPLC (Condition 4) t_(R)=5.48 min, UPLC-MS (Condition 3)t_(R)=1.04 min, m/z=269 [M+H]⁺.

Example 279(R)-6-(3-Hydroxypyrrolidin-1-yl)-5-(pyrimidin-5-yl)-N-(6-((trifluoromethyl)thio)pyridin-3-yl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 169 using(R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(6-((trifluoromethyl)thio)pyridin-3-yl)nicotinamide(Stage 279.1) and pyrimidin-5-ylboronic acid to afford a white resinouspowder. HPLC (Condition 4) t_(R)=4.41 min, UPLC-MS (Condition 3)t_(R)=0.83 min, m/z=463.2 [M+H]⁺; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm1.68-1.93 (m, 2H) 2.91 (d, J=11.34 Hz, 1H) 3.20-3.44 (m, 3H) 4.22 (br.s, 1H) 4.90 (d, J=3.52 Hz, 1H) 7.81 (d, J=8.60 Hz, 1H) 8.07-8.16 (m, 1H)8.29-8.38 (m, 1H) 8.80-8.85 (m, 1H) 8.90 (s, 2H) 8.95-9.03 (m, 1H)9.17-9.24 (m, 1H) 10.44 (s, 1H).

Stage 279.1(R)-5-Bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(6-((trifluoromethyl)thio)pyridin-3-yl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Stage 171.1 using5-bromo-6-chloro-N-(6-((trifluoromethyl)thio)pyridin-3-yl)nicotinamide(Stage 279.2) and (R)-pyrrolidin-3-ol to afford an off-white powder.HPLC (Condition 4) t_(R)=5.53 min, UPLC-MS (Condition 3) t_(R)=1.01 min,m/z=463.1 [M+H]⁺.

Stage 279.25-Bromo-6-chloro-N-(6-((trifluoromethyl)thio)pyridin-3-yl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Stage 169.2 using 5-bromo-6-chloronicotinic acid and6-(trifluoromethylthio)pyridin-3-amine to afford an off-white powder.HPLC (Condition 4) t_(R)=6.43 min, UPLC-MS (Condition 3) t_(R)=1.15 min,m/z=411.9 [M−H]⁻.

Example 280(R)—N-(4-(Chlorodifluoromethoxy)phenyl)-4′-fluoro-2-(3-hydroxypyrrolidin-1-yl)-[3,3′-bipyridine]-5-carboxamide

(R)-5-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide(Stage 171.1, 116 mg, 0.25 mmol) and4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (116mg, 0.5 mmol) were dissolved in DME (1 mL). A solution of 2 M Na₂CO₃(0.375 mL, 0.75 mmol) was added, the mixture was flushed with argon andPdCl₂(dppf) (9 mg, 0.013 mmol) was added and the RM was stirred at 120°C. for 1 h. Additional4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (80 mg)and PdCl₂(dppf) (9 mg, 0.013 mmol) were then added and the RM wasstirred at 120° C. for further 45 min. After cooling at RT, the RM wastreated with EtOAc, washed with brine dried over Na₂SO₄. The solvent wasevaporated under reduced pressure to give a residue that was purified byflash chromatography (RediSep® Silica gel column, 12 g, EtOAc/2% MeOH inEtOAc, gradient 50 to 100% B, EtOAc/MeOH 10%) and treated with Si-Thiol(100 mg) in MeOH. The product was further purified by preparative SFC(Column Diol, from 21% to 26% in 6 min) to afford the title product as abeige foam. HPLC (Condition 4) t_(R)=5.14 min, UPLC-MS (Condition 3)t_(R)=0.98 min, m/z=479.2 [M+H]⁺; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm1.66-1.94 (m, 2H) 2.89-3.00 (m, 1H) 3.14-3.23 (m, 1H) 3.23-3.42 (m, 3H)4.20 (br. s, 1H) 4.88 (br. s, 1H) 7.34 (d, J=8.60 Hz, 2H) 7.47 (dd,J=9.78, 5.47 Hz, 1H) 7.81-7.90 (m, 2H) 8.05 (d, J=2.35 Hz, 1H) 8.62-8.79(m, 2H) 8.81 (d, J=2.35 Hz, 1H) 10.17 (s, 1H).

Example 2816-(5-(2-Hydroxyethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

To a solution of6-chloro-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide(Stage 223.1, 100 mg, 0.253 mmol) in DMF (2 mL) were added K₂CO₃ (105mg, 0.760 mmol) and tert-butylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (81 mg, 0.380 mmol).The RM was stirred at 110° C. for 4 h and then at 130° C. for 5 h. Afterremoval of solvent under reduced pressure, the crude intermediate wastreated with a mixture of TFA/DCM (1 mL/2 mL) at RT for 5 h. The solventwas evaporated off under reduced pressure to afford6-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide,a portion of which (100 mg, 0.213 mmol) was dissolved in anhydrous THF(2 mL) and was treated with KOtBu (71.6 mg, 0.638 mmol) and2-bromoethanol (0.1 mL, 1.435 mmol). The RM was stirred at 70° C.overnight, the solvent was evaporated off under reduced pressure and thecrude material was purified by preparative HPLC. The compound waslyophilized in water/MeCN to afford the title product. UPLC-MS(Condition 3), t_(R)=0.77 min, m/z=515.2 [M+H]⁺.

Example 282N-(4-(Chlorodifluoromethoxy)phenyl)-6-((3R,4R)-3,4-dihydroxypyrrolidin-1-yl)-5-(4-methylpyrimidin-5-yl)nicotinamide

N-(4-(chlorodifluoromethoxy)phenyl)-6-((3R,4R)-3,4-dihydroxypyrrolidin-1-yl)-5-iodonicotinamide(Stage 282.1, 100 mg, 0.190 mmol) and4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine(Stage 297.1, 62.8 mg, 0.285 mmol), Pd(Ph₃P)₄ (21.98 mg, 0.019 mmol) andK₂CO₃ (79 mg, 0.571 mmol) were added to a vial and flushed with argon.DMF (2 mL) was added and the mixture was stirred at 100° C. for 2 h. Thesolvent was evaporated off under reduced pressure. The crude product wasdissolved in MeOH, filtered through a PL-resin Si-Thiol cartridge, thecartridge was washed with MeOH and the solvent was evaporated off underreduced pressure to give a residue which was purified by preparativeHPLC (Condition 14-25% to 55% MeCN in 20 min) and followed bypreparative SFC (Column Diol, from 20% to 25% in 6 min). The purifiedproduct was lyophilized in water/min vol. MeCN to afford the titleproduct as a white powder. UPLC-MS (Condition 3), t_(R)=0.86 min,m/z=492.2/494.2 [M+H]⁺.

Stage 282.1N-(4-(Chlorodifluoromethoxy)phenyl)-6-((3R,4R)-3,4-dihydroxypyrrolidin-1-yl)-5-iodonicotinamide

To a solution of6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-iodonicotinamide (Stage247.2, 300 mg, 0.654 mmol) and (3R,4R)-pyrrolidine-3,4-diol (88 mg,0.850 mmol) in iPrOH (5 mL) was added DIPEA (0.228 mL, 1.307 mmol). TheRM was stirred at 140° C. for 1 h and then 3 h at 130° C. The solventwas evaporated off under reduced pressure to give the crude productwhich was used directly without any further purification. UPLC-MS(Condition 3), t_(R)=1.00 min, m/z=525.9/528.0 [M+H]⁺.

Example 283N-(4-(Chlorodifluoromethoxy)phenyl)-6-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)-5-(4-methylpyrimidin-5-yl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 290 using5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)nicotinamideand (3S,4S)-pyrrolidine-3,4-diol to afford a white solid. HPLC(Condition 10) t_(R)=5.517 min, UPLC-MS (Condition 3) t_(R)=0.88 min,m/z=492.1 [M+H]⁺; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 2.16 (s, 3H) 2.96 (br.s, 2H) 3.19-3.37 (m, 2H) 3.86 (br. s, 2H) 5.07 (br. s, 1H) 5.75 (br. s,1H) 7.34 (d, J=7.43 Hz, 2H) 7.86 (d, J=7.82 Hz, 2H) 7.94-8.10 (m, 1H)8.29-9.13 (m, 3H) 10.05-10.25 (m, 1H).

Example 2842-(trans-3-Amino-4-methoxypyrrolidin-1-yl)-N-(4-(chlorodifluoromethoxy)phenyl)-5′-fluoro-[3,3′-bipyridine]-5-carboxamide

2-Chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5′-fluoro-[3,3′-bipyridine]-5-carboxamide(Stage 266.1, 70 mg, 0.160 mmol) and DIPEA (0.196 mL, 1.121 mmol) wereadded to a vial containing iPrOH (1 mL) andtrans-4-methoxypyrrolidin-3-amine dihydrochloride (Stage 284.1, 32.5 mg,0.168 mmol) was added under argon atmosphere. The RM was stirred at 110°C. for 40 h. The RM was treated with sat. aq. Na₂CO₃ (20 mL) andextracted with EtOAc. The combined extracts were washed with brine (10mL), dried over Na₂SO₄, filtered and the filtrate was evaporated offunder reduced pressure to give the crude product which was purified bypreparative HPLC (Condition 14). Fractions containing product weretreated with sat. aq. Na₂CO₃ and the MeCN was evaporated off underreduced pressure. The aq. phase was extracted with EtOAc. The combinedorganic layers were dried over Na₂SO₄, filtered and the filtrate wasevaporated off under reduced pressure to give a residue which wassuspended in DCM/n-hexane. The obtained solid was filtered off, washedwith n-hexane and dried to afford the title product as a white solid.HPLC (Condition 10) t_(R)=6.11 min, UPLC-MS (Condition 3) t_(R)=0.86min, m/z=508.2/510.1 [M+H]⁺; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.63 (br.s, 2H) 2.83-2.90 (m, 1H) 3.03-3.11 (m, 1H) 3.20-3.22 (m, 3H) 3.27-3.35(m, 2H) 3.48-3.56 (m, 2H) 7.34 (d, J=8.21 Hz, 2H) 7.80-7.90 (m, 3H) 8.08(d, J=2.35 Hz, 1H) 8.51 (s, 1H) 8.60 (d, J=2.74 Hz, 1H) 8.75-8.80 (m,1H) 10.18 (s, 1H).

Stage 284.1 trans-4-Methoxypyrrolidin-3-amine dihydrochloride

The title compound was prepared in an analogous fashion to thatdescribed in Stage 245.2 using tert-butyltrans-3-amino-4-methoxy-1-pyrrolidinecarboxylate hydrochloride.

Example 2854-((3S,4S)-3-Amino-4-hydroxypyrrolidin-1-yl)-N-(4-(chlorodifluoromethoxy)phenyl)-3-(5-fluoropyridin-3-yl)benzamide

4-((3S,4S)-3-Amino-4-hydroxypyrrolidin-1-yl)-3-bromo-N-(4-(chlorodifluoromethoxy)phenyl)benzamide(Stage 245.1, 60 mg, 0.122 mmol), 3-fluoropyridine-5-boronic acidpinacol ester and Na₂CO₃ (0.183 mL, 0.366 mmol) were added to a vialcontaining DME (1 mL) under an argon atmosphere. PdCl₂(dppf)-(CH₂Cl₂)(5.98 mg, 7.33 μmol) was added and the RM was stirred at 80° C. for 1.5h. The RM was filtered through Hyflo® and the solvent was evaporated offunder reduced pressure to give the crude product which was purified byflash chromatography (Silica gel column, DCM/MeOH, from 98:2 to 8:2).Fractions containing product were combined and the solvent wasevaporated off under reduced pressure to give a residue which wassuspended in DCM/n-hexane, filtered, washed with n-hexane and werepurified by preparative HPLC (Condition 14). Fractions containing pureproduct were combined, treated with sat. aq. Na₂CO₃ and the MeCN wasevaporated off under reduced pressure. The aq. residue was extractedwith EtOAc. The combined extracts were washed with brine, dried overNa₂SO₄, filtered and the filtrate was evaporated off under reducedpressure to give a residue which was suspended in DCM/n-hexane 1:5 andfiltered to afford the title product as a white solid. HPLC (Condition10) t_(R)=6.01 min, UPLC-MS (Condition 3) t_(R)=0.84 min,m/z=493.1/495.2 [M+H]⁺; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.61 (br. s, 2H)2.63-2.74 (m, 2H) 3.12 (br. s, 1H) 3.22-3.31 (m, 2H) 3.74 (br. s, 1H)4.98 (d, J=3.52 Hz, 1H) 6.93 (d, J=8.60 Hz, 1H) 7.33 (d, J=8.99 Hz, 2H)7.78 (d, J=9.77 Hz, 1H) 7.86 (m, J=9.00 Hz, 3H) 7.92 (dd, J=8.80, 2.15Hz, 1H) 8.50 (s, 1H) 8.56 (d, J=2.74 Hz, 1H) 10.10 (s, 1H).

Example 2862-(trans-3-Amino-4-methoxypyrrolidin-1-yl)-5′-fluoro-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 284 using2-chloro-5′-fluoro-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide(Stage 236.1) and trans-4-methoxypyrrolidin-3-amine dihydrochloride(Stage 284.1, 20 h at 80° C. then 24 h at 100° C.). HPLC (Condition 10)t_(R)=5.97 min, UPLC-MS (Condition 3) t_(R)=0.83 min, m/z=492.2 [M+H]⁺;¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.62 (br. s, 2H) 2.82-2.90 (m, 1H)3.02-3.11 (m, 1H) 3.21 (s, 3H) 3.26-3.34 (m, 2H) 3.47-3.57 (m, 2H) 7.35(d, J=8.99 Hz, 2H) 7.85 (m, J=9.00 Hz, 3H) 8.08 (d, J=2.35 Hz, 1H) 8.51(s, 1H) 8.60 (d, J=2.74 Hz, 1H) 8.77 (d, J=1.95 Hz, 1H) 10.17 (s, 1H).

Example 287(R)—N-(4-(Chlorodifluoromethoxy)phenyl)-5-(2-cyano-5-fluorophenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide

(R)-5-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide(Stage 171.1, 50 mg, 0.108 mmol),4-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (32mg, 0.130 mmol), PdCl₂(dppf) (7.91 mg, 10.81 μmol) and K₃PO₄ (68.8 mg,0.324 mmol) were added to a vial and flushed with argon. Dioxane (1 mL)was added and the mixture was stirred at 120° C. for 1.5 h. The solventwas evaporated off under reduced pressure and the crude product waspurified by preparative SFC (Column 2-EP, from 17% to 22% in 6 min). Thepurified product was lyophilized in water/min. vol. MeCN to afford thetitle product as a slightly yellow powder. UPLC-MS (Condition 3),t_(R)=1.09 min, m/z=503.1/505.2 [M+H]⁺.

Example 288(R)-2′-Chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5′-fluoro-2-(3-hydroxypyrrolidin-1-yl)-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 287 using(R)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide(Stage 171.1) and2-chloro-5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridineto afford a slightly rose powder. UPLC-MS (Condition 3), t_(R)=1.09 min,m/z=513.2/515.1 [M+H]⁺; ¹H-NMR (600 MHz, DMSO-d₆) δ ppm 1.67-1.96 (m,2H) 2.86-3.50 (m, 4H) 4.14-4.29 (m, 1H) 7.33 (d, J=8.78 Hz, 2H) 7.85 (d,J=9.15 Hz, 2H) 7.97-8.02 (m, 1H) 8.02-8.21 (m, J=8.42, 2.93 Hz, 1H) 8.55(t, J=3.11 Hz, 1H) 8.81 (dd, J=7.68, 2.20 Hz, 1H) 10.17 (s, 1H).

Example 289(R)-6-(3-Amino-3-(trifluoromethyl)pyrrolidin-1-yl)-N-(4-(chlorodifluoromethoxy)phenyl)-5-(pyrimidin-5-yl)nicotinamide

A stirred mixture of6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(pyrimidin-5-yl)nicotinamide(Stage 247.1, 150 mg, 0.365 mmol) in iPrOH (0.5 mL) was treated withtert-butyl[3-(trifluoromethylpyrrolidine-3-yl)]carbamate (179 mg, 0.547mmol) and DIPEA (0.159 mL, 0.912 mmol) were added at RT. The resultingmixture was stirred at 140° C. for 12 h. The solution was diluted inEtOAc (50 mL), washed with a 2 N citric acid solution (20 mL), aq. sat.solution of NaHCO₃ (20 mL) and brine (20 mL), dried over Na₂SO₄,filtered and the solvent was evaporated off under reduced pressure togive the crude product which was purified by flash chromatography(RediSep® Silica gel column, 40 g, DCM/MeOH 95:5). Obtained(R)-tert-butyl(1-(5-((4-(chlorodifluoromethoxy)phenyl)carbamoyl)-3-(pyrimidin-5-yl)pyridin-2-yl)-3-(trifluoromethyl)pyrrolidin-3-yl)carbamate(137 mg, 0.196 mmol) was suspended in DCM (1 mL) and TFA (0.453 mL, 5.88mmol) was added at RT. The resulting light yellow solution was stirredfor 1.5 h at RT. The RM was diluted with EtOAc (50 mL), then washed withan aq. sat. solution of NaHCO3 and twice with water (2×20 mL). Theaqueous phase was extracted with EtOAc (40 mL). The combined organicphases were dried over sodium sulfate, filtered and concentrated underreduced pressure. The crude product was purified by flash chromatography(RediSep® Silica gel, 12 g, DCM/MeOH 95:5). The obtained residuere-suspended in MeOH (2 mL) was stirred at RT for 15 min. The crystalswere filtered and washed with MeOH (2 mL) to afford the title product asa white solid. HPLC (Condition 10) t_(R)=5.92 min, UPLC-MS (Condition 3)t_(R)=1.05 min, m/z=529.2 [M+H]⁺; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm1.76-1.85 (m, 1H) 2.02 (s, 1H) 2.24-2.35 (m, 2H) 3.13-3.27 (m, 2H)3.37-3.52 (m, 2H) 7.35 (d, J=8.60 Hz, 2H) 7.86 (m, J=9.00 Hz, 2H) 8.14(d, J=2.35 Hz, 1H) 8.81 (d, J=2.35 Hz, 1H) 8.92 (s, 2H) 9.22 (s, 1H)10.23 (s, 1H).

Example 290N-(4-(Chlorodifluoromethoxy)phenyl)-4′-cyano-2-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)-[3,3′-bipyridine]-5-carboxamide

4-Cyanopyridine-3-boronic acid pinacol ester (192 mg, 0.836 mmol), K₂CO₃(0.418 mL, 0.836 mmol) and Pd(PPh₃)₄ (24.14 mg, 0.021 mmol) were addedto a solution of5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)nicotinamide(Stage 248.1, 200 mg, 0.418 mmol) in DMF (2.5 mL) in a vial at RT. Thevial was evacuated/purged with argon, sealed and heated at 130° C. for18 h. The RM was diluted with EtOAc (60 mL) and washed with an aq. sat.solution of NaHCO₃ (20 mL) and brine (2×20 mL). The organic phase wasdried over Na₂SO₄, filtered and the solvent was evaporated off underreduced pressure. The resulting residue was suspended in MeOH (3 mL),stirred for at RT 15 min, filtered and washed with MeOH (2 mL). Thefiltrate was filtered through a SPE PL-Thiol cartridge (StratoSpheres™,500 mg, nominal:1.5 mmol) and the solvent was evaporated off underreduced pressure to give a residue which was purified by preparative SFC(Column 2-EP, from 21% to 26% in 6 min) to afford the title product as ayellow solid. HPLC (Condition 10) t_(R)=5.90 min, UPLC-MS (Condition 3)t_(R)=0.94 min, m/z=502.2 [M+H]⁺; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 2.95(d, J=11.34 Hz, 2H) 3.14-3.39 (m, 2H) 3.86 (br. s, 2H) 5.02-5.07 (m, 1H)5.09-5.14 (m, 1H) 7.34 (d, J=8.60 Hz, 2H) 7.86 (d, J=8.60 Hz, 2H)7.96-8.06 (m, 1H) 8.12 (d, J=17.60 Hz, 1H) 8.76-8.88 (m, 2H) 9.08 (br.s, 1H) 10.21 (d, J=4.69 Hz, 1H).

Example 291(R)—N-(4-(Chlorodifluoromethoxy)phenyl)-2-(3-hydroxypyrrolidin-1-yl)-4′-methyl-[3,3′-bipyridine]-5-carboxamide

(R)-5-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide(Stage 171.1, 70 mg, 0.151 mmol),4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (49.7mg, 0.227 mmol), Pd(Ph₃P)₄ (17.48 mg, 0.015 mmol) and K₃PO₄ (96 mg,0.454 mmol) were added to a vial, flushed with argon, treated withtoluene (1 mL), and stirred at 110° C. for 2 h followed by 4 h at 130°C. Dioxane (1 mL) was added and the RM was stirred for an additional 3days at 130° C. The RM was diluted with dioxane and filtered on a pad ofHyflo®, followed by Si-Thiol scavenger treatment. The solvent wasevaporated off under reduced pressure and the crude product was purifiedby preparative SFC (Column Diol, from 20% to 25% in 6 min). The purifiedproduct was lyophilized in water/min. vol. MeCN to afford the titleproduct as an off-white powder. UPLC-MS (Condition 3), t_(R)=0.97 min,m/z=475.1/477.1 [M+H]⁺; ¹H-NMR (600 MHz, DMSO-d₆) δ ppm 1.62-1.89 (m,2H) 2.02/2.14 (s, 3H) 2.70-3.35 (m, 4H) 4.09-4.24 (m, 1H) 4.79-4.96 (m,1H) 7.27-7.42 (m, J=8.66 Hz, 3H) 7.86 (d, J=7.91 Hz, 2H) 7.91-8.00 (m,1H) 8.41-8.61 (m, 2H) 8.77 (br. s, 1H) 10.11-10.19 (m, 1H).

Example 292(R)—N-(4-(Chlorodifluoromethoxy)phenyl)-2′-cyano-5′-fluoro-2-(3-hydroxypyrrolidin-1-yl)-[3,3′-bipyridine]-5-carboxamide

(R)-2′-Chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5′-fluoro-2-(3-hydroxypyrrolidin-1-yl)-[3,3′-bipyridine]-5-carboxamide(Example 288, 100 mg, 0.195 mmol), Pd(Ph₃P)₄ (22.51 mg, 0.019 mmol),zinc cyanide (114 mg, 0.974 mmol) were added to a vial, flushed withargon, treated with DMF (2 mL) and stirred for 18 h at 130° C. Thesolvent was evaporated off under reduced pressure and the residue waspurified by preparative SFC (Column NH₂, from 16% to 21% in 6 min). Thefractions containing product were combined and the solvent wasevaporated off under reduced pressure to give a residue which waslyophilized in water/min. vol. MeCN to afford the title product as anoff-white powder. UPLC-MS (Condition 3), t_(R)=1.09 min, m/z=504.1/506.1[M+H]⁺; ¹H-NMR (600 MHz, DMSO-d₆) δ ppm 1.70-1.97 (m, 2H) 2.80-2.94 (m,1H) 3.09-3.23 (m, 1H) 3.23-3.38 (m, 2H) 4.16-4.29 (m, 1H) 4.85-5.02 (m,1H) 7.35 (d, J=8.47 Hz, 2H) 7.86 (d, J=8.28 Hz, 2H) 8.08-8.37 (m, 2H)8.86 (d, J=6.96 Hz, 2H) 10.24 (br. s, 1H).

Example 293(R)—N-(4-(Chlorodifluoromethoxy)phenyl)-5-(3-cyano-5-fluorophenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 290 using(R)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide(Stage 171.1) and 3-Cyano-5-Fluorophenylboronic acid to afford a whitesolid. HPLC (Condition 10) t_(R)=6.383 min, UPLC-MS (Condition 11)m/z=503.1 [M+H]⁺; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.69-1.80 (m, 1H)1.81-1.93 (m, 1H) 2.86 (d, J=10.95 Hz, 1H) 3.14-3.29 (m, 2H) 3.35-3.49(m, 1H) 4.21 (br. s, 1H) 4.87 (d, J=3.52 Hz, 1H) 7.34 (d, J=8.60 Hz, 2H)7.67 (d, J=9.38 Hz, 1H) 7.79 (s, 1H) 7.83-7.91 (m, J=8.99 Hz, 3H) 8.06(d, J=1.96 Hz, 1H) 8.77 (d, J=2.35 Hz, 1H) 10.17 (s, 1H).

Example 294(R)—N-(4-(Chlorodifluoromethoxy)phenyl)-5-(5-fluoro-2-methylphenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 290 using(R)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide(Stage 171.1) and 5-Fluoro-2-methylphenylboronic acid to afford a whitesolid. HPLC (Condition 10) t_(R)=6.424 min, UPLC-MS (Condition 11)m/z=492.1 [M+H]⁺; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.60-1.92 (m, 2H)1.94-2.11 (m, 3H) 2.78-3.03 (m, 1H) 3.07-3.28 (m, 3H) 4.11-4.23 (m, 1H)4.76-4.94 (m, 1H) 7.10-7.19 (m, 1H) 7.23-7.31 (m, 1H) 7.33 (d, J=8.99Hz, 3H) 7.86 (d, J=8.99 Hz, 2H) 7.91 (m, J=2.30 Hz, 1H) 8.73-8.79 (m,1H) 10.08-10.17 (m, 1H).

Example 295(R)—N-(4-(Chlorodifluoromethoxy)phenyl)-5-(5-cyano-2-fluorophenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide

5-Cyano-2-fluorophenylboronic acid (53.5 mg, 0.324 mmol), K₃PO₄ (138 mg,0.648 mmol) and PdCl₂(dppf)-(CH₂Cl₂) (17.65 mg, 0.022 mmol) were addedto(R)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide(Stage 171.1,) in dioxane (1.5 mL) in a vial at RT. The vial wasevacuated/purged with argon, sealed and stirred at 130° C. for 2.5 h.The RM was diluted with EtOAc (60 mL), washed with an aq. sat. solutionof NaHCO₃ (20 mL) and brine (2×20 mL). The organic phase was dried overNa₂SO₄, filtered, and the solvent was evaporated off under reducedpressure. The residue was dissolved in MeOH (3 mL), filtered through aSPE PL-Thiol cartridge (StratoSpheres™, 500 mg, nominal:1.5 mmol), thecartridge was washed with MeOH and the solvent was evaporated off underreduced pressure to give a residue which was purified by preparative SFC(Column 2-EP, from 18% to 23% in 6 min) to afford the title product as awhite solid. HPLC (Condition 10) t_(R)=6.31 min, UPLC-MS (Condition 3)t_(R)=1.12 min, m/z=503.1 [M+H]⁺; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm1.64-2.01 (m, 2H) 2.93 (br. s, 1H) 3.19 (dd, J=11.14, 4.11 Hz, 1H)3.23-3.43 (m, 2H) 4.21 (br. s, 1H) 4.84 (br. s, 1H) 7.34 (d, J=8.99 Hz,3H) 7.57 (br. s, 1H) 7.80-7.91 (m, 3H) 7.94-8.24 (m, 4H) 8.79 (d, J=1.96Hz, 1H) 10.16 (s, 1H).

Example 296N-(4-(Chlorodifluoromethoxy)phenyl)-6-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)-5-(5-fluoro-2-methylphenyl)nicotinamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 290 using5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)nicotinamide(Stage 248.1) and 5-fluoro-2-methylphenylboronic acid to afford a whitesolid. HPLC (Condition 10) t_(R)=6.25 min, UPLC-MS (Condition 11)t_(R)=1.08 min, m/z=508.1 [M+H]⁺; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm1.59-1.90 (s, 2H) 1.95/2.06 (s, 3H) 2.76-3.00 (m, 1H) 3.04-3.25 (m, 2H)4.09-4.21 (m, 1H) 4.76-4.90 (m, 2H) 7.08-7.17 (m, 1H) 7.25-7.35 (m, 4H)7.81-7.97 (m, 3H) 8.74 (s, 1H) 10.07-10.17 (m, 1H).

Example 297N-(4-(Chlorodifluoromethoxy)phenyl)-4-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)-3-(4-methylpyrimidin-5-yl)benzamide

4-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine(Stage 297.1, 94 mg, 0.429 mmol), K₂CO₃ (118 mg, 0.857 mmol) andPd(PPh₃)₄ (33.0 mg, 0.029 mmol) were added to a solution of3-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)benzamide(Stage 244.1, 150 mg, 0.286 mmol) in DMF (2.5 mL). at RT in a vial. Thevial was evacuated/purged with argon, sealed and stirred at 130° C. for2 h. The RM was diluted in EtOAc (80 mL), washed with water (3×30 mL),dried over Na₂SO₄, filtered, and the solvent was evaporated off underreduced pressure. The residue was dissolved in methanol (3 mL) andfiltered through a SPE PL-Thiol cartridge (StratoSpheres™, 500 mg,nominal:1.5 mmol), the cartridge was washed with MeOH and the solventwas evaporated off under reduced pressure to give a residue which waspurified by preparative SFC (Column 2-EP, from 20% to 25% in 6 min) andby preparative HPLC. The obtained residue was treated with a aq.solution of Na₂CO₃ (3 mL) and extracted twice with EtOAc (2×30 mL). Thecombined organic phases were washed with water (2×15 mL), dried overNa₂SO₄, filtered, and the solvent was evaporated off under reducedpressure to afford the title product as a beige solid. HPLC (Condition10) t_(R)=6.091 min, UPLC-MS (Condition 11) t_(R)=0.93 min, m/z=491.1[M+H]⁺; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 2.19/2.40 (s, 3H) 2.65-2.78 (m,2H) 3.06-3.22 (m, 2H) 3.80-3.90 (m, 2H) 5.01-5.12 (m, 2H) 6.93 (d,J=8.99 Hz, 1H) 7.32 (d, J=8.60 Hz, 2H) 7.70-7.80 (m, 1H) 7.83-7.89 (d,J=8.60 Hz, 2H) 7.91-7.98 (m, 1H) 8.82 (s, 1H) 9.05 (s, 1H) 10.01-10.12(m, 1H).

Stage 297.14-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine

A mixture of 5-bromo-4-methylpyrimidine (470 mg, 2.72 mmol),PdCl₂(dppf)₂ (199 mg, 0.272 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1035 mg,4.07 mmol) and KOAc (800 mg, 8.15 mmol) in anhydrous dioxane (15 mL) wasstirred overnight at 90° C. The RM was filtered through Hyflo® and thesolvent was evaporated off under reduced pressure. The residue wasdissolved in EtOAc, washed with brine, dried over Na₂SO₄, filtered andthe filtrate was evaporated off under reduced pressure to afford thecrude title product as a dark solid. UPLC-MS (Condition 3), t_(R)=0.30min, m/z=139.0 [M+H]⁺, 137.1 [M−H]⁻.

Example 298(R)—N-(4-(Chlorodifluoromethoxy)phenyl)-5-(2,4-dimethoxypyrimidin-5-yl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide

(R)-5-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide(Stage 171.1, 150 mg, 0.324 mmol), 2,4-dimethoxypyrimidin-5-ylboronicacid (71.6 mg, 0.389 mmol), PdCl₂(dppf)-(CH₂Cl₂) (39.7 mg, 0.049 mmol)and K₃PO₄ (206 mg, 0.973 mmol) were added to a vial and flushed withargon. Dioxane (1.5 mL) was added and the mixture was stirred at 120° C.overnight. The solvent was evaporated off under reduced pressure, theresidue was treated with Si-Thiol (Biotage, load: 1.3 mmol/g) in MeOHand purified by preparative SFC (Column DEAP, from 18% to 23% in 6 min)to afford the title compound as an off-white powder after lyophilizationfrom water/MeCN. UPLC-MS (Condition 11), t_(R)=1.05 min, m/z=522.3/524.2[M+H]⁺; ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.66-1.92 (m, 2H) 2.89-3.43 (m,4H) 3.91 (br. s, 3H) 3.95 (s, 3H) 4.21 (br. s, 1H) 4.74-5.00 (m, 1H)7.33 (d, J=8.91 Hz, 2H) 7.83-7.90 (m, 3H) 8.32 (br. s, 1H) 8.74 (d,J=2.26 Hz, 1H) 10.11 (s, 1H).

Example 299(R)—N-(4-(Chlorodifluoromethoxy)phenyl)-5′-cyano-2-(3-hydroxypyrrolidin-1-yl)-6′-methoxy-[3,3′-bipyridine]-5-carboxamide

The title compound was prepared in an analogous fashion to thatdescribed in Example 298 using(R)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide(Stage 171.1) and2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrileto afford an off-white powder. UPLC-MS (Condition 11), t_(R)=1.13 min,m/z=516.2/518.2 [M+H]⁺; ¹H-NMR (600 MHz, DMSO-d₆) δ ppm 1.67-1.78 (m,1H) 1.79-1.93 (m, 1H) 2.90 (d, J=11.29 Hz, 1H) 3.19-3.29 (m, 2H)3.35-3.43 (m, 1H) 4.06 (s, 3H) 4.21 (br. s, 1H) 4.90 (br. s, 1H) 7.33(d, J=8.66 Hz, 2H) 7.85 (d, J=8.85 Hz, 2H) 8.02 (d, J=1.88 Hz, 1H) 8.35(s, 1H) 8.50 (s, 1H) 8.77 (d, J=1.88 Hz, 1H) 10.18 (s, 1H).

Assays

The utility of the compounds of the invention described herein can beevidenced by testing in the following assays. Compounds of the inventionwere assessed for their ability to inhibit ABL1 activity in biochemicalassays and BCR-ABL1 in cellular assays described below.

Biochemical Assays

Expression and Purification of Protein Kinase—

Expression and purification of human ABL was performed using standardexpression purification procedures. The ABL64-515 protein was generatedand used for in vitro kinase assays. The protein was generated by aco-expression vector carrying the DNA fragments for ABL1 (la isoform,with an N-terminal His6-tag followed by a PreScission protease cleavagesite) and the human protein tyrosine phosphatase-1B (residues 1-283,untagged), using the dual expression vector pCDF Duet-1 (Novagen). TheHis-ABL was expressed in E. coli BL21 (DE3) and the ABL proteins wereisolated by Ni-affinity on a Ni-NTA column (Qiagen). The His-tag wasremoved by PreScission protease (GE Healthcare) and thenon-phosphoprylated ABL further purified on a Mono Q HR 10/10 (GEHealthcare, mono-phosphorylated ABL is about 10-20% of total ABLprotein) and HiLoad 16/60 Superdex 200 size exclusion column (GEHealthcare). Non-phosphorylated ABL64-515 proteins were analyzed by massspectroscopic analysis and flash-frozen in aliquots and stored at −80°C. SRC (amino acids 83-535 or Src83-535) was expressed and purified asdescribed (S. W. Cowan-Jacob, G. Fendrich, P. W. Manley, W. Jahnke, D.Fabbro, J. Liebetanz, T. Meyer, c-Src crystal structure providesinsights into c-Src activation. Structure 13 (2005) 861-871).

Radio ABL1 (64-515) Assay

For determination of ABL kinase activity, the radiometric filter-bindingassay was used. The assay was performed by mixing 10 μL of the compoundpre-diluted with 10 μL of ATP (20 μM ATP with 0.1 μCi [γ-33P]-ATP) withthe phospho-acceptor peptide poly[Ala6Glu2LysHBr5Tyr1]=polyAEKY) in 20mM Tris/HCl pH 7.5, 1 mM DTT, 10 mM MgCl₂, 0.01 mM Na₃VO₄, 50 mM NaCl.10 μL of enzyme (ranging between 5 nM to 20 nM) was added to initiatethe reaction. Pre-incubation of enzyme with compounds (when stated) wasperformed by exposing the enzyme to compounds prior to addition of thesubstrate mixture (ATP and/or peptide substrate). After 15 mM at roomtemperature, the reaction was stopped by the addition of 50 μL 125 mMEDTA, and the peptide-bound 33P separated on filter-plates (PVDF orMAIP; Millipore, Volketswil, Switzerland) prepared according to themanufacturer's instructions. Filter-plates were washed 3× with 0.5%H₃PO₄, followed by addition of 30 μL scintillation cocktail (Microscint,Perkin Elmer) per well and then analysed in a TopCount NXT scintillationcounter (Perkin Elmer). Results were expressed as IC₅₀ values. The K_(m)values for ATP were determined by assaying the ABL kinase withincreasing concentrations of ATP and keeping the exogenous acceptorprotein substrate (poly-AEKY) at a constant concentration (at about2-fold its K_(m)) and vice versa. K_(m) and V_(max) were calculatedaccording to Eadie-Hofstee as described (D. Fabbro, G. Fendrich, V.Guez, T. Meyer, P. Furet, J. Mestan, J. D. Griffin, P. W. Manley, S. W.Cowan-Jacob, Targeted therapy with imatinib: An exception or a rule?Handbook of Experimental Pharmacology 167, Inhibitors of Protein Kinasesand Protein Phosphates (2005) 361-389). The data were plotted as Vversus V/S, where V is the velocity of the reaction at a given substrate(S) concentration, and fitted to a straight line using linear regressionanalysis, where the slope of the line corresponds to −K_(m) and theY-intercept represents the V_(max).

Caliper ABL1 (64-515) Assay

All assays were performed in 384-well microtiter plates. Each assayplate contained 8-point serial dilutions for 40 test compounds, as wellas four 8-point serial dilutions of staurosporine as a referencecompound, plus 16 high and 16 low controls. Liquid handling andincubation steps were done on a Thermo CatX workstation equipped withInnovadyne Nanodrop Express. Between pipetting steps, tips were cleanedin wash cycles using wash buffer.

The assay plates were prepared by addition of 50 nL per well of compoundsolution in 90% DMSO. The kinase reactions were started by stepwiseaddition of 4.5 μL per well of peptide/ATP-solution (50 mM HEPES, pH7.5, 1 mM DTT, 0.02% BSA, 0.6% DMSO, 10 mM beta-glycerophosphate, and 10μM sodium orthovanadate, 20 mM MgCl₂, 2 mM MnCl₂, 4 μM ATP, 4 μM peptide(FITC-Ahx-EAIYAAPFAKKK-NH2)) and 4.5 μL per well of enzyme solution (50mM HEPES, pH 7.5, 1 mM DTT, 0.02% BSA, 0.6% DMSO, 10 mMbeta-glycerophosphate, and 10 μM sodium orthovanadate, 20 mM MgCl₂, 2 mMMnCl₂, 3.5 nM ABL (ABL(64-515), produced in-house from E. coli)). Kinasereactions were incubated at 30° C. for 60 minutes and subsequentlyterminated by addition of 16 μL per well of stop solution (100 mM HEPESpH 7.5, 5% DMSO, 0.1% Caliper coating reagent, 10 mM EDTA, and 0.015%Brij35). Plates with terminated kinase reactions were transferred to theCaliper LC3000 workstations for reading. Phosphorylated andunphosphorylated peptides were separated using the Caliper microfluidicmobility shift technology. Briefly, samples from terminated kinasereactions were applied to the chip. Analytes are transported through thechip by constant buffer flow and the migration of the substrate peptideis monitored by the fluorescence signal of its label. Phosphorylatedpeptide (product) and unphosphorylated peptide (substrate) are separatedin an electric field by their charge/mass ratio. Kinase activities werecalculated from the amounts of formed phospho-peptide. IC50 values weredetermined from percent inhibition values at different compoundconcentrations by non-linear regression analysis.

Preparation of Compound Dilutions:

Test compounds were dissolved in DMSO (10 mM) and transferred into 1.4mL flat bottom or V-shaped Matrix tubes carrying a unique 2D matrix. Thestock solutions were stored at +2° C. if not used immediately. For thetest procedure the vials were defrosted and identified by a scannerwhereby a working sheet was generated that guided the subsequent workingsteps.

Compound dilutions were made in 96-well plates. This format enabled theassay of maximally 40 individual test compounds at 8 concentrations(single points) including 4 reference compounds. The dilution protocolincluded the production of “pre-dilution plates”, “master plates” and“assay plates”.

Pre-Dilution Plates:

Polypropylene 96-well plates were used as pre-dilution plates. A totalof 4 pre-dilution plates were prepared including 10 test compounds eachon the plate positions A1-A10, one standard compound at A11 and one DMSOcontrol at A12. All dilution steps were done on a HamiltonSTAR robot.

Master Plates:

30 μL of individual compound dilutions including standard compound andcontrols of the 4 “pre-dilution plates” were transferred into a 384“master plate” including the following concentrations 1′810, 362, 72.5,54.6, 14.5, 2.9, 0.58 and 0.120/1, respectively in 90% of DMSO.

Assay Plates:

Identical “assay plates” were then prepared by pipetting 50 nL each ofcompound dilutions of the “master plates” into 384-well “assay plates”by means of a HummingBird 384-channel dispenser. These plates were useddirectly for the assay which was performed in a total volume of 9.05 μL.This led to a final compound concentration of 10, 2.0, 0.4, 0.08, 0.016,0.0032, 0.00064 and 0.000128 μM and a final DMSO concentration of 0.5%in the assay.

Cellular Assays

To assess the ability of compounds of the invention to inhibit BCR-ABL1activity in cellular assays, compounds were evaluated for their abilityto selectively inhibit the proliferation of cells dependent on BCR-ABL1expression relative to cells that do not depend on BCR-ABL1 expression.

The murine bone marrow-derived cell line Ba/F3 was used to generate theappropriate cell line models. Ba/F3 cells were obtained from the GermanCollection of Microorganisms and Cell Cultures (DSMZ, Braunschweig andDSMZ No. ACC 300). Parental Ba/F3 cells depend on IL3 for growth andsurvival and were used as the reference cell line that does not dependon BCR-ABL1 activity for growth and survival. These cells are referredto as Ba/F3-WT.

To generate Ba/F3 cells that depend on BCR-ABL1 expression for growthand survival, Ba/F3 cells were engineered to express BCR-ABL1 usingretroviral transduction with a MSCV based retroviral vector containing ap210 BCR-ABL1 expression cassette. When grown in the absence of IL-3,the proliferation of the cells is dependent on the expression ofBCR-ABL1. (Daley, G. Q. and Baltimore, D. Transformation of aninterleukin 3-dependent hematopoietic cell line by the chronic myeloidleukemia-specific p210 BCR-ABL1 protein. PNAS 1988; 85:9312-9316). Thesecells are referred to as Ba/F3-BCR-ABL-WT. A similar approach was usedto generate Ba/F3 cells that depend on a BCR-ABL1 variant in whichthreonine 315 is replaced with isoleucine. These cells are referred toas Ba/F3-BCR-ABL-T315I.

Ba/F3-WT cells were maintained in RPMI1640 media with L-glutamine, HEPES(Lonza), 10% FBS (Gibco) and 5 ng/ml IL-3 (Calbiochem).Ba/F3-BCR-ABL1-WT cells and Ba/F3-BCR-ABL1-T315I cells were maintainedin RPMI1640 media with L-glutamine, HEPES (Lonza) and 10% FBS (Gibco).

Proliferation Assay

For each cell line, the cell density was adjusted to 50 000 cells/mL and50 μL (2500 cells) added per well of a 384-well assay plate.

Test compounds were resuspended in DMSO at a concentration of 10 mM. Aserial three-fold dilution of each compound with DMSO was performed in384-well plates using the Janus Liquid Dispenser (PerkinElmer). Compoundwas delivered to the assay plates containing 2500 cells in a 50 μLvolume via Acoustic delivery from an ATS-100 (EDC). ForBa/F3-BCR-ABL1-WT cell assays, 2 nL of each compound dilution wastransferred to the assay plate for final assay concentrations of 0.4 μM,0.13 μM, 0.044 μM, 0.015 μM, 0.005 μM, 0.001 μM, 0.00033 μM, 0.00011 μM,0.000037 μM, 0.000012 μM. For Ba/F3-WT and Ba/F3-BCR-ABL1-T315I cellassays, 50 nL of each compound dilution was transferred to the assayplate for final assay concentrations of 10 μM, 3.33 μM, 1.11 μM, 0.37μM, 0.12 μM, 0.041 μM, 0.014 μM, 0.0046 μM, 0.0015 μM, 0.00051 μM.

Cells were incubated at 37° C. in a humidified environment with 5%carbon dioxide for 48 hours. Britelite plus solution (Perkin Elmer) wasprepared according to the manufacturer's instructions and 25 μL added toeach well of the assay plate. Plates were incubated for 3-5 minutes andthe luminescence detected on an EnVision Multimode plate reader (PerkinElmer). The degree of luminescence correlates with the number of cellsin each well. The effect of each inhibitor concentration can thereforebe calculated and IC₅₀ values generated.

The compounds of the invention show IC₅₀ values in the range of 0.1 nMto 20 nM for inhibition of Abl kinase activity in a radiometric filterbinding (Radio). For a microfluidic mobilitiy shift assays (Caliper)assay, IC₅₀ values can be found in the range of 0.1 nM to 20 nM. ForBa/F3-BCR-ABL-WT and T315I cellular proliferation assay, GI₅₀ values canbe found in the range of 0.5 nM to 50 nM and 10 nM to 2000 nM,respectively.

Radio ABL1 (64- Caliper ABL1 (64- Example 515) IC₅₀ [μM] 515) IC₅₀ [μM]Table of biochemical data part I 1 <0.003 2 <0.003 3 <0.003 4 0.007 5<0.003 0.0027 6 <0.003 7 <0.003 0.0012 8 0.013 0.0028 9 0.017 0.0018 100.003 0.0022 11 <0.003 12 0.01 13 0.0033 14 <0.003 15 <0.003 16 <0.00317 <0.003 18 <0.003 19 <0.003 20 <0.003 21 0.013 22 <0.003 23 <0.003 24<0.003 25 <0.003 0.0019 26 <0.003 27 <0.003 28 <0.003 29 <0.003 30<0.003 31 0.007 32 <0.003 33 0.009 0.0048 34 <0.003 0.0008 35 <0.0030.0012 36 <0.003 37 0.003 38 0.004 0.0014 39 <0.003 0.0006 40 0.00020.0022 41 <0.003 0.0008 42 <0.003 0.0008 43 0.005 44 <0.003 45 <0.0030.0011 46 0.003 0.004 47 0.003 0.0012 48 0.0042 0.0008 49 0.005 0.003550 0.003 0.0011 51 <0.003 0.0029 52 <0.003 0.0006 53 <0.003 0.0004 540.005 0.0009 55 0.003 56 0.004 57 0.007 58 0.004 0.0006 59 0.006 600.004 0.006 61 0.004 0.0005 62 0.004 0.0021 63 0.004 64 <0.003 65 <0.0030.0035 66 <0.003 0.0004 67 <0.003 68 <0.003 0.0009 69 <0.003 0.0005 70<0.003 0.0004 71 0.002 0.0034 72 <0.003 0.0011 73 0.015 0.014 74 0.0060.004 75 <0.003 0.0006 76 <0.003 77 0.003 0.0009 78 <0.003 0.0002 790.004 0.001 80 0.005 81 <0.003 82 <0.003 0.0006 83 0.011 84 0.003 0.001185 0.026 86 0.0063 0.0006 87 0.006 0.0007 88 0.004 <0.00013 89 <0.0030.0003 90 <0.003 0.0007 91 0.005 92 0.006 0.0007 93 0.006 0.0014 94<0.003 95 <0.003 96 <0.003 0.0028 97 <0.003 98 0.007 99 <0.003 100<0.003 101 <0.003 102 <0.003 0.0023 Table of biochemical data part II103 <0.003 104 0.003 105 <0.003 0.0006 106 <0.003 107 <0.003 108 <0.0030.0003 109 <0.003 110 0.005 111 <0.003 112 <0.003 113 <0.003 0.0015 1140.006 115 0.016 116 <0.003 0.0035 117 0.0004 0.0055 118 <0.003 119 0.004120 <0.003 121 <0.003 0.0011 122 0.005 123 0.017 124 <0.003 0.0006 125<0.003 0.0012 126 0.003 127 0.004 0.0011 128 <0.003 0.0023 129 0.0080.0054 130 0.003 0.0012 131 0.0084 0.0013 132 <0.003 0.0015 133 <0.0030.0014 134 0.01 135 <0.003 0.002 136 <0.003 137 0.006 0.0006 138 0.0070.0008 139 0.005 0.0006 140 0.004 0.0004 141 0.006 142 0.006 143 0.0040.0011 144 0.005 145 0.004 146 <0.003 147 <0.003 148 0.003 0.0025 1490.003 0.0026 150 0.004 0.0065 151 <0.003 <0.00013 152 0.0054 153 <0.003154 <0.003 0.001 155 0.011 0.005 156 0.005 0.0017 157 <0.003 0.002 1580.037 0.0028 159 <0.003 160 <0.003 161 0.012 162 0.012 163 <0.003 1640.012 165 <0.003 166 0.042 167 0.03 168 <0.003 169 0.0011 0.0008 170<0.003 <0.00013 171 0.004 <0.00013 172 <0.003 0.0003 173 0.003 <0.00013174 0.003 0.0009 175 0.0005 0.0002 176 0.011 0.0006 177 0.001 0.0003 1780.013 0.0004 179 0.002 0.0008 180 0.001 0.0004 181 0.004 0.0002 1820.004 0.0006 183 0.002 0.0005 184 0.006 0.0008 185 0.0024 0.0002 1860.005 0.0002 187 0.004 0.0002 188 0.004 0.0002 189 0.003 0.001 1900.0059 0.0005 191 0.008 0.0009 192 0.002 0.0013 193 0.0023 0.0004 1940.005 0.0014 195 0.003 <0.00013 196 0.0051 0.0007 197 0.016 0.0018 198<0.003 0.0004 199 0.003 0.0012 200 0.004 0.0012 201 0.004 0.0019 2020.0034 0.0007 203 0.001 0.0009 204 <0.003 0.0043 Table of biochemicaldata part III 205 <0.003 <0.00013 206 0.006 0.0005 207 0.003 0.0011 208<0.003 0.0006 209 <0.003 0.0005 210 0.004 0.0008 211 0.011 0.0033 2120.007 0.011 213 0.007 0.016 214 0.008 0.0081 215 0.0012 0.0079 216 0.0030.0007 217 0.002 0.0004 218 0.003 0.0006 219 0.016 0.016 220 0.0060.0023 221 0.01 0.0013 222 0.011 0.015 223 0.0002 0.01 224 0.0016 0.0047225 0.002 0.0085 226 0.0019 227 0.0009 0.0016 228 0.001 0.0011 229 0.0010.0024 230 0.0039 0.0061 231 0.001 0.0059 232 0.006 0.0053 233 0.00240.004 234 0.019 235 0.002 0.0018 236 0.003 0.0014 237 0.0006 0.0012 2380.002 0.0026 239 0.004 0.0026 240 0.002 0.0014 241 0.0017 0.0013 2420.006 0.0045 243 0.0013 0.0005 244 0.001 0.0006 245 0.005 0.001 2460.001 0.0022 247 0.0019 <0.00013 248 0.001 <0.00013 249 0.001 0.0007 2500.001 0.0013 251 <0.0001 0.0007 252 0.0083 0.0005 253 0.002 0.0005 254<0.0001 0.0006 255 0.0021 0.0011 256 0.002 0.0004 257 0.003 0.0006 2580.0027 0.0011 259 0.0051 <0.00013 260 0.0051 0.001 261 0.0018 0.0039 2620.002 0.0007 263 0.003 <0.00013 264 0.001 0.0006 265 0.003 <0.00013 2660.007 0.0024 267 0.0013 0.0006 268 0.0005 0.0004 269 <0.0001 <0.00013270 0.002 0.0006 271 0.0005 0.0007 272 0.004 0.0011 273 0.002 0.0012 274<0.0001 0.0004 275 0.005 0.0028 276 0.003 0.0068 277 0.002 0.0017 2780.001 0.0005 279 0.003 0.008 280 0.0020 0.0003 281 0.0110 282 0.0009 2840.0010 0.0008 285 0.0010 0.0006 286 0.0020 0.0017 287 0.0015 288 0.0010289 0.0030 0.0007 290 0.0020 0.0008 291 0.0002 292 0.0005 293 0.0007 2940.0030 295 0.0007 296 0.0010 297 0.0014 298 0.002 299 0.0003

Table of Cellular Proliferation Data Ba/F3-BCR-ABL1-WT and T315IBa/F3-BCR-ABL1- Ba/F3-BCR-ABL1- Example WT IC₅₀ [μM] T315I IC₅₀ [μM] 20.0024 0.124 4 0.0056 0.633 35 0.0029 0.088 57 0.0066 1.117 105 0.01250.800 129 0.0102 0.513 142 0.0089 0.855 170 0.0005 0.013 171 0.00050.012 181 0.0014 0.038 186 0.0007 0.019 187 0.0008 0.024 201 0.01290.273 208 0.0039 0.130 212 0.047 0.442 215 0.0246 0.554 216 0.0074 0.169218 0.0009 0.010 222 0.0435 0.580 248 0.009 0.213 249 0.0049 0.130 2570.0011 0.038 268 0.0032 0.093 278 0.0009 0.024 283 0.0216 0.370 2850.0053 0.165 297 0.0013 0.035 298 0.0022 0.036

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application andscope of the appended claims.

1. A compound of formula (I):

in which: Y at each occurrence is independently selected from N and CH;R₁ is selected from pyrimidinyl, pyridinyl, phenyl, quinoxalinyl andisoquinolinyl; wherein said pyrimidinyl, pyridinyl, phenyl, quinoxalinyland isoquinolinyl of R₁ is unsubstituted or substituted with 1 to 3 R₆groups; R₂ is selected from pyrrolidinyl, piperidinyl, azetidinyl,morpholino, piperazinyl, 2-oxa-6-azaspiro[3.4]-octanyl,3-azabicyclo[3.1.0]hexan-3-yl,pyrrolo[3,4-c]pyrazol-5(1H,4H,6H)-yl,hexahydropyrrolo[3,4-c]pyrrolyl,6-oxo-2,7-diazaspiro[4.4]-nonanyl, 1H-pyrrolo[3,4-c]pyridinyl,1,4-oxazepan-4-yl, 2-oxooxazolidinyl, 1,4-diazepanyl,tetrahydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl,3,8-dioxa-10-azabicyclo[4.3.1]decanyl and —NR_(5a)R_(5b); wherein saidpyrrolidinyl, piperidinyl, azetidinyl, morpholino, piperazinyl,1,4-oxazepan-4-yl, pyrrolo[3,4-c]pyrazol-5(1H,4H,6H)-yl,2-oxa-6-azaspiro[3.4]-octanyl, 3-azabicyclo[3.1.0]hexan-3-yl,hexahydropyrrolo[3,4-c]pyrrolyl, 6-oxo-2,7-diazaspiro[4.4]-nonanyl,1H-pyrrolo[3,4-c]pyridinyl, 2-oxooxazolidinyl, 1,4-diazepanyl,tetrahydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl, or3,8-dioxa-10-azabicyclo[4.3.1]decanyl is unsubstituted or substitutedwith 1 to 3 R₇ groups; R₃ is selected from hydrogen and halo; R₄ isselected from —SF₅ and —Y₂—CF₂—Y₃; R_(5a) is selected from hydrogen andmethyl; R_(5b) is selected from C₁₋₄alkyl and tetrahydro-2H-pyran-4-yl;wherein said alkyl of R_(5b) is unsubstituted or substituted with 1 to 3groups independently selected from hydroxy and dimethyl-amino; R₆ ateach occurrence is independently selected from methyl, methoxy, cyano,trifluoromethyl, methoxy-carbonyl, 2-hydroxypropan-2-yl, hydroxy-methyl,halo, amino, fluoro-ethyl, ethyl and cyclopropyl; R₇ at each occurrenceis independently selected from hydroxy, methyl, methoxy, hydroxy-methyl,amino, methyl-amino, amino-methyl, trifluoromethyl,2-hydroxypropan-2-yl, methyl-carbonyl-amino, dimethyl-amino, cyano andamino-carbonyl; or two R₇ groups combine with the atom to which they areattached to form a ring selected from cyclopropyl,pyrrolo[3,4-c]pyrazol-5(1H,4H,6H)-yl and 3-azabicyclo[3.1.0]hexan-3-yl;wherein said 3-azabicyclo[3.1.0]hexan-3-yl can be optionally substitutedwith amino; Y₁ is selected from N and CR₅; wherein R₅ is selected fromhydrogen, methoxy and imidazolyl; wherein said imidazolyl isunsubstituted or substituted with methyl; Y₂ is selected from CF₂, O andS(O)₀₋₂; and Y₃ is selected from hydrogen, halo, methyl, difluoromethyland trifluoromethyl; or the pharmaceutically acceptable salts thereof.2. The compound of claim 1 of formula (Ia):

in which: R₄ is selected from —SF₅ and —Y₂—CF₂—Y₃; R₆ at each occurrenceis independently selected from hydrogen, methyl, methoxy, cyano,trifluoromethyl, methoxy-carbonyl, 2-hydroxypropan-2-yl, hydroxy-methyl,halo, amino, fluoro-ethyl, ethyl and cyclopropyl; R₇ at each occurrenceis independently selected from hydroxy, methyl, methoxy, hydroxy-methyl,amino, methyl-amino, amino-methyl, trifluoromethyl,2-hydroxypropan-2-yl, methyl-carbonyl-amino, dimethyl-amino, cyano andamino-carbonyl; or two R₇ groups combine with the atom to which they areattached to form a ring selected from cyclopropyl,pyrrolo[3,4-c]pyrazol-5(1H,4H,6H)-yl and 3-azabicyclo[3.1.0]hexan-3-yl;wherein said 3-azabicyclo[3.1.0]hexan-3-yl can be optionally substitutedwith amino; Y₁ is selected from N and CR₅; wherein R₅ is selected fromhydrogen, methoxy and imidazolyl; wherein said imidazolyl isunsubstituted or substituted with methyl; Y₂ is selected from CF₂, O andS(O)₀₋₂; and Y₃ is selected from hydrogen, halo, methyl, difluoromethyland trifluoromethyl; Y₄ is selected from CR₆ and N; or thepharmaceutically acceptable salts thereof.
 3. The compound of claim 2 offormula (Ib):

in which: R₄ is selected from —SF₅ and —Y₂—CF₂—Y₃; R₆ at each occurrenceis independently selected from hydrogen, methyl, methoxy, cyano,trifluoromethyl, methoxy-carbonyl, 2-hydroxypropan-2-yl, hydroxy-methyl,halo, amino, fluoro-ethyl, ethyl and cyclopropyl; R₇ at each occurrenceis independently selected from hydroxy, methyl, methoxy, hydroxy-methyl,amino, methyl-amino, amino-methyl, trifluoromethyl,2-hydroxypropan-2-yl, methyl-carbonyl-amino, dimethyl-amino, cyano andamino-carbonyl; or two R₇ groups combine with the atom to which they areattached to form a ring selected from cyclopropyl,pyrrolo[3,4-c]pyrazol-5(1H,4H,6H)-yl and 3-azabicyclo[3.1.0]hexan-3-yl;wherein said 3-azabicyclo[3.1.0]hexan-3-yl can be optionally substitutedwith amino; Y₁ is selected from CH and N; Y₂ is selected from CF₂, O andS(O)₀₋₂; Y₃ is selected from hydrogen, fluoro, chloro, methyl,difluoromethyl and trifluoromethyl; or the pharmaceutically acceptablesalts thereof.
 4. (canceled)
 5. The compound of claim 4 selected from:


6. (canceled)
 7. The compound of claim 2 selected from:


8. (canceled)
 9. The compound of claim 2 selected from:


10. The compound of claim 2 of formula (Ic):

in which: R₄ is selected from —SF₅ and —Y₂—CF₂—Y₃; R₆ at each occurrenceis independently selected from hydrogen, methyl, methoxy, cyano,trifluoromethyl, methoxy-carbonyl, 2-hydroxypropan-2-yl, hydroxy-methyl,halo, amino, fluoro-ethyl, ethyl and cyclopropyl; R₇ at each occurrenceis independently selected from hydroxy, methyl, methoxy, hydroxy-methyl,amino, methyl-amino, amino-methyl, trifluoromethyl,2-hydroxypropan-2-yl, methyl-carbonyl-amino, dimethyl-amino, cyano andamino-carbonyl; or two R₇ groups combine with the atom to which they areattached to form a ring selected from cyclopropyl and3-azabicyclo[3.1.0]hexan-3-yl; Y₁ is selected from CH and N; Y₂ isselected from CF₂, O and S(O)₀₋₂; Y₃ is selected from hydrogen, fluoro,chloro, methyl, difluoromethyl and trifluoromethyl; or thepharmaceutically acceptable salts thereof.
 11. (canceled)
 12. Thecompound of claim 1 selected from:


13. (canceled)
 14. The compound of claim 1 selected from:


15. The compound of claim 2 of formula (Id):

in which: R₄ is selected from —SF₅ and —Y₂—CF₂—Y₃; R₆ at each occurrenceis independently selected from hydrogen, methyl, methoxy,methoxy-carbonyl, 2-hydroxypropan-2-yl, cyano, trifluoromethyl,hydroxy-methyl, halo, amino, fluoro-ethyl, ethyl and cyclopropyl; R₇ ateach occurrence is independently selected from hydroxy, methyl, methoxy,hydroxy-methyl, amino, methyl-amino, amino-methyl, trifluoromethyl,2-hydroxypropan-2-yl, methyl-carbonyl-amino, dimethyl-amino, cyano andamino-carbonyl; or two R₇ groups combine with the atom to which they areattached to form a ring selected from cyclopropyl and3-azabicyclo[3.1.0]hexan-3-yl; Y₁ is selected from CH and N; Y₂ isselected from CF₂, O and S(O)₀₋₂; Y₃ is selected from hydrogen, fluoro,chloro, methyl, difluoromethyl and trifluoromethyl; or thepharmaceutically acceptable salts thereof.
 16. The compound of claim 15selected from:


17. The compound of claim 2 of formula (Ie):

in which: R₄ is selected from —SF₅ and —Y₂—CF₂—Y₃; R₆ at each occurrenceis independently selected from hydrogen, methyl, methoxy, cyano,trifluoromethyl, methoxy-carbonyl, 2-hydroxypropan-2-yl, hydroxy-methyl,halo, amino, fluoro-ethyl, ethyl and cyclopropyl; R₇ at each occurrenceis independently selected from hydroxy, methyl, methoxy, hydroxy-methyl,amino, methyl-amino, amino-methyl, trifluoromethyl,2-hydroxypropan-2-yl, methyl-carbonyl-amino, dimethyl-amino, cyano andamino-carbonyl; or two R₇ groups combine with the atom to which they areattached to form a ring selected from cyclopropyl and3-azabicyclo[3.1.0]hexan-3-yl; Y₁ is selected from CH and N; Y₂ isselected from CF₂, O and S(O)₀₋₂; Y₃ is selected from hydrogen, fluoro,chloro, methyl, difluoromethyl and trifluoromethyl; or thepharmaceutically acceptable salts thereof.
 18. The compound of claim 17selected from:


19. (canceled)
 20. The compound of claim 2 selected from:


21. (canceled)
 22. The compound of claim 2 selected from:

23-29. (canceled)
 30. A pharmaceutical composition comprising a compoundof claim 1, admixed with at least one pharmaceutically acceptableexcipient selected from the group consisting of corn starch, potatostarch, tapioca starch, starch paste, pre-gelatinized starch, sugars,gelatin, natural gums, synthetic gums, sodium alginate, alginic acid,tragacanth, guar gum, cellulose, ethyl cellulose, cellulose acetate,carboxymethyl cellulose calcium, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, microcrystalline cellulose,magnesium aluminum silicate, polyvinyl pyrrolidone, talc, calciumcarbonate, powdered cellulose, dextrates, kaolin, mannitol, silicicacid, sorbitol, agar-agar, sodium carbonate, croscarmellose sodium,crospovidone, polacrilin potassium, sodium starch glycolate, clays,sodium stearate, calcium stearate, magnesium stearate, stearic acid,mineral oil, light mineral oil, glycerin, sorbitol, mannitol,polyethylene glycol, other glycols, sodium laurel sulfate, hydrogenatedvegetable oil, peanut oil, cottonseed oil, sunflower oil, sesame oil,olive oil, corn oil, soybean oil, zinc stearate, sodium oleate, ethyloleate, ethyl laureate, silica, and combinations thereof.
 31. (canceled)32. The pharmaceutical composition of claim 30, further comprising anadditional therapeutic agent selected from an anticancer compound, ananalgesic, an antiemetic, an antidepressant, and an anti-inflammatoryagent; wherein said anticancer compound is a BCR-ABL1 inhibitor selectedfrom imatinib, nilotinib, dasatinib, bosutinib, ponatinib and bafetinib.33. (canceled)
 34. A method to treat cancer, comprising administering toa subject in need of such treatment an effective amount of a compound ofclaim 1 or a pharmaceutical composition of claim 30; wherein said canceris selected from lung carcinoma, pancreatic carcinoma, bladdercarcinoma, colon carcinoma, myeloid disorders, prostate cancer, thyroidcancer, melanoma, adenomas and carcinomas of the ovary, eye, liver,biliary tract, and nervous system.
 35. (canceled)
 36. The method ofclaim 34, further comprising administering to the subject an additionaltherapeutic agent selected from an anticancer drug, a pain medication,an antiemetic, an antidepressant or an anti-inflammatory agent; whereinsaid anticancer agent is a BCR-ABL1 inhibitor is selected from imatinib,nilotinib, dasatinib, bosutinib, ponatinib and bafetinib. 37-45.(canceled)